NF-κB and Poultry

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1		Peter Surai	--	6725	2022-06-10 10:54:26	\|
2	format correct	Vivi Li	+ 39 word(s)	6764	2022-06-10 11:54:03	\|

This entry is adapted from the peer-reviewed paper 10.3390/antiox10020186

antioxidants NF-κB oxidative stress poultry redox balance

1. Introduction

Redox biology is a very quickly developing area of modern biological sciences, and roles of redox homeostasis in health and disease have recently received tremendous attention ^[1]^[2]^[3]^[4]^[5]^[6]. There are a range of redox pairs in cells/tissues responsible for redox homeostasis maintenance/regulation. They include, but are not limited to, NAD⁺/NADH, NADP⁺/NADPH, GSSH/GSH (glutathione system), Trx^ox/Trx^red (thioredoxin system), protein thiols^ox/protein thiols^red. It is believed that redox signaling is tightly integrated with various homeostatic mechanisms ^[7] and all redox elements are interconnected and regulated by various means, including antioxidant and vitagene networks ^[1]. The redox status is responsible for maintenance of cell signaling and cell stress adaptation. There are a range of redox sensors which determine redox imbalance and activate various pathways for its re-establishment. Among them are proteins Keap1, an inhibitor of Nrf2, and IκB, an inhibitor of NF-κB, which have received a lot of recent attention. Indeed, oxidation of SH groups in Cys of Keap1 or phosphorylation of IκB are important triggers for nuclear translocation and activation of Nrf2 and NF-κB—important players in the redox homeostasis regulation ^[6]. In particular, a recent model suggests regulation of all collaborating metabolic organs in the body through changes in circulating redox metabolites ^[5].

The physiological roles of redox homeostasis maintenance in avian species, including poultry, are poorly characterized. However, for the last 5 years, this topic attracted a lot of attention, and a range of publications covered some related aspects. Indeed, the redox system imbalance is shown to be associated with protein oxidation and impaired quality of poultry meat ^[8]^[9]. In broilers, subjected to dietary and heat stress, magnesium supplementation was indicated to improve redox status and meat quality ^[10]. The influence of selenium and selenoproteins in maintaining redox balance and immune responses of poultry and pigs was presented ^[11], and the effect of oxidative stress and redox disbalance on inflammation, including a detailed immune system investigation, was discussed ^[12]^[13]. Oxidative stress-related disturbances of the redox balance in the poultry gut have also been described ^[13]^[14]^[15]^[16]. The long-term effects of Ochratoxin A on the glutathione redox system in chickens have been investigated ^[17], and the protective effects of milk thistle on redox-homeostasis imbalance of duck liver imposed by mycotoxins ^[18] were shown. Furthermore, the detrimental effects of heavy metals (e.g., As) on redox imbalance in chickens have been reported ^[19]. Nutritional modulation of the antioxidant capacities and redox homeostasis in poultry by selenium ^[13]^[20], vitamin E ^[21], and carotenoids ^[22], including astaxanthin ^[23], has been described. Recently, the vitagene concept of stress adaptation was developed, and questions related to redox balance maintenance in poultry under various stress conditions were addressed ^[1]. In fact, the vitagene family includes superoxide dismutase (SOD), heat shock protein 70 (HSP70), heme oxygenase 1(HO-1), elements of thioredoxin and glutathione systems, and sirtuins ^[24]^[25]^[26]. Indeed, induction/activation of the aforementioned genes leading to synthesis/expression of protective molecules helps animals/poultry adapt to stress by using their internal resources to the maximum extent.

2. NF-κB in Poultry Production

The regulatory roles of NF-κB in poultry are still poorly understood, but accumulating information clearly indicates that, similar to mammals, NF-κB is a main regulator of many important processes, including inflammation in avian species. In 1993, complementary DNA (cDNA) clones encoding the chicken NF-κB p65 subunit were isolated, and, according to the information provided by the authors, chicken NF-κB can be briefly characterized as follows ^[27]:

Chicken p65 was shown to be approximately 55% identical to the mouse and human p65 proteins. Similar to its mammalian counterpart, chicken p65 contains the Rel homology domain (RHD) in its N-terminal consisting of 286 amino acids and the putative transactivation domain in its C-terminal region;
It was proven that the RHD was highly conserved between the chicken and mammalian p65 proteins;
The highest expression of a 2.6 kb transcript of p65 was detected in the spleen. It was also detected in other organs;
A fusion protein containing the RHD of chicken p65 was reported to bind to a consensus kappa B-site;
p65 was shown to form one or more complexes with various cellular proteins, including p50, p105, and c-Rel in chicken spleen cells ^[27].

Furthermore, the cDNA clones encoding chicken p50B/p97 were isolated ^[28]. The amino-acid sequence of the precursor protein p97 was found to be characterized by a conserved structure. In particular, it was shown to have 86% identity in the RHD and lower (56%) identity in the ankyrin repeat domain (ARD) to human p50B/p97. Similar to previous findings, expression of this gene was also found to be highest in the chicken spleen ^[28]. In 1995 from a chicken genomic library, a clone containing the avian I kappa B-alpha gene was isolated ^[29]. Main characteristics of I kappa B-alpha can be summarized as follows: recognizable promoter elements (i.e., TATA and CAAT boxes) were not found in avian I kappa B-α. There were seven putative Rel/NF-kappa B binding sites in avian I kappa B-α. When transfected into cells which produce I kappa B-α, a CAT reporter construct containing the 5′ upstream region of I kappa B-α was expressed. The regulatory elements promoting I kappa B-α expression were identified within 1000 nt of the transcription start site. I kappa B-alpha was shown to be found as a single-copy gene per haploid genome. This gene was expressed in avian hematopoietic tissues and in lymphoid cells transformed by avian reticuloendotheliosis virus ^[29]. It was suggested that, similar to mammals, in chicken, p65 and c-Rel comprise components of the protein complexes that are able to bind to the kappa B-like sequence. This binding could lead to the progressively activated expression of the chicken lysozyme gene observed during the terminal differentiation of macrophages ^[30].

In 2001, Piffat et al. constructed and characterized a composite cDNA encoding most of the chicken RelB transcription factors ^[31], and their results can be summarized as follows: within the RH domain, chicken RelB (cRelB) protein was characterized by a high degree of sequence similarity to other vertebrate RelB proteins. However, outside this domain, cRelB was substantially less conserved. cRelB was found to be more widely expressed than mammalian RelB, and it was identified to have functional properties similar to other vertebrate RelB proteins. cRelB was reported to be unable to bind DNA in a homodimer form; however, it could form DNA-binding heterodimers with NF-kappaB p50 or p52. Overexpressed cRelB was shown to be present in the nucleus in chicken embryo fibroblasts. The nonconserved C-terminal sequences of cRelB contained a transactivation domain found in chicken and mouse fibroblasts ^[31]. A new isoform of chicken myeloid differentiation factor 88 (MyD88-2) expression was detected in a range of tissues tested and its overexpression was found to significantly induce the activation of NF-κB in vitro ^[32]. Recently the duck IKKα (duIKKα) gene was cloned and characterized. In fact, DuIKKα was reported to encode a protein containing 757 amino acids and having high sequence identities with the goose IKKα. Duck liver and heart were characterized by a high expression of duIKKα messenger RNA (mRNA), while its expression was reported in all tested tissues, including muscular stomach, spleen, heart, liver, lung, kidney, cerebellum, cerebrum, windpipe, muscle, glandular stomach, thymus, duodenum, cecum, pancreas, and bursa of Fabricius ^[33]. An important role of du IKKα in NF-κB regulation has been demonstrated by increasing or inhibiting expression of duIKKα. On the one hand, overexpression of duIKKα was shown to substantially increase NF-κB activity with subsequent induction of cytokines interferon beta (IFN-β), IL-1β, IL-6, and IL-8 in duck embryo fibroblasts. On the other hand, knockdown of duIKKα was found to significantly decrease LPS-, poly(I:C)-, poly(dA:dT)-, duck enteritis virus (DEV)-, or duck Tembusu virus (DTMUV)-induced NF-κB activation ^[33]. It seems likely that IKKα is evolutionarily conserved. In fact, phosphorylation of Ser176 and Ser180 in the active center of IKKα is believed to be vital to IKKα activation, and those Ser residues were shown to be well conserved among mammals, birds, and fish ^[33].

It was shown that the NF-κB family of transcription factors contribute to activation-induced cytidine deaminase-mediated gene conversion in chickens ^[34]. Gallus heat-shock cognate protein 70 was shown to regulate RelA/p65 gene expression induced by Apoptin, a nonstructural protein of chicken anemia virus ^[35]. In chicken heterophils, bacterial TLR agonists were indicated to activate NF-κB-mediated leukotriene B4 and prostaglandin E2 production ^[36]. A switchlike response in NF-κB activity is based on the existence of a threshold in the NF-κB signaling module, and phosphorylation of the Ser-578 residue of the scaffolding protein caspase recruitment domain (CARD)-containing protein 1 (CARMA1) was shown to account for the feedback ^[37]. It is known that tumor necrosis factor receptor-associated factors (TRAFs) are responsible for activation of various signaling cascades, being key regulatory proteins in NF-κB signaling pathways ^[38]. It seems likely that avian TRAFs play important roles in defending against both RNA and DNA virus infection. In fact, chicken TRAF3 (chTRAF3) was shown to encode a protein of 567 amino acids with high identity to TRAF3 homologs from mammals being abundantly expressed in the spleen, thymus, lung, and small intestine ^[39]. Of note, the authors showed that Newcastle disease virus F48E9 challenge was responsible for TRAF3 suppression in chicken embryo fibroblast cells. Recently, the full-length duck TRAF6 (duTRAF6) cDNA from embryo fibroblasts was cloned, and it was shown that duTRAF6 was widely expressed in different tissues. Interestingly, overexpression of duTRAF6 was found to activate NF-κB and induce interferon-β expression ^[40]. It has been shown that goose TRAF6 shared similar features with the TRAF6 of other avian species, being an essential regulator for inducing the activity of NF-κB and playing important roles in innate immune response ^[41]. The amino-acid sequence of pigeon FRAF6 (piTRAF6) was shown to share a strong identity with that of other birds. Furthermore, piTRAF6 expression was shown in all examined tissues, including heart, lung, spleen, thigh muscle, large intestine, caecum, kidney small intestine, brain, bursa of Fabricius, rib, and muscular stomach ^[42]. The heart was characterized by the highest level of piTRAF6 transcript, and the muscular stomach had the lowest level of piTAF6 transcript. On the one hand, overexpression of piTRAF6 was shown to induce NF-κB in a dose-dependent manner with increased IFN-β expression. On the other hand, piTRAF6 knockdown was reported to suppress NF-κB activation in HEK293T cells ^[42]. Furthermore, the pigeon TRAF3 (PiTRAF3) gene was reported to be highly expressed in the spleen, lung, kidney, brain, thymus, and muscle, while a moderate expression was observed in the small and large intestines, with relatively weak expression in the heart and liver ^[43].

Among the five major families of pattern recognition receptors (PRRs), Toll-like receptors (TLRs) and nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs), in particular, NOD1, recently received major attention in relation to their roles in avian immunity via NF-κB regulation. Indeed, NF-κB is considered to be the major transcription factor involved downstream of the TLR signaling pathway ^[44]. Avian TLRs are shown to be different from their mammalian counterparts: absence of TLR8 and TLR9, along with presence of TLR1La, TLR1Lb, TLR15, and TLR21 ^[45]. Therefore, in chickens, 10 TLR receptor genes were identified: TLR1LA, TLR1LB, TLR2B, TLR2A, TLR3, TLR4, TLR5, TLR7, TLR15 ^[46], and TLR21 ^[47]. Among them, TLR1LA, TLR1LB, TLR2A, TLR2B, TLR4, TLR5, and TLR15 are responsible for bacterial component (lipoproteins, peptidoglycans, LPS, and flagellin) detection, while TLR3 and TLR7 detect viruses (double-stranded RNA (dsRNA), single-stranded RNA (ssRNA), imidazoquinoline compounds), and TRL21 detects CpG oligodeoxynucleotides in viruses and bacteria ^[47]. Initially, it was reported that chicken TLR2 and TLR4 can mediate LPS-stimulated oxidative burst, while CD14 and TLR2 are involved in the mediation of lipoteichoic acid-stimulated oxidative burst in heterophils ^[48]. The tissue-specific expression of chicken TLRs (TLR2A, TLR3, TLR4, TLR5, TLR7, TLR15, and TLR21) during embryonic development was evaluated and early (third embryonic day) expression of all the TLR mRNAs was reported ^[49]. Furthermore, TLR1 (type 1 and 2), TLR2 (type 1 and 2), and TLRs 3–5, 7, 15, and 21 were shown to be expressed in the chicken follicular theca. The connection of the TLRs to NF-κB was proven experimentally; the expression of IL-1β, IL-6, chemotactic and angiogenic factor (CXCLi2), and IFN-β in tissues incubated with LPS was downregulated by an inhibitor of NF-κB ^[44].

It seems likely that NF-κB is involved in the activation of avian antimicrobial peptides. For example, chicken intestine defensins (e.g., AvBD13) were suggested to be endogenous ligands for TLR4 able to enhance the proliferation of monocytes via the NF-κB pathway ^[50]. It should be mentioned that cathelicidins (CATHs), short cationic host defense peptides, also act in close concert with NF-κB. Indeed, in macrophages primed by LPS, pigeon CATH2 was shown to act through MAPK and NF-κB signaling pathways to enhance expression of the anti-inflammatory cytokine, while downregulating the expressions of inducible nitric oxide synthase and proinflammatory cytokines and inhibiting the TLR4 pathway ^[51]. Furthermore, NK-lysin/granulysin (NKL), an antimicrobial cationic peptide expressed in natural killer cells and cytotoxic T lymphocytes, was identified in different avian species, including chicken, turkey, zebra finch, and quail, and the 5′ flanking region of quail NKL was shown to contain two NF-κB-binding sites ^[52], suggesting participation of NF-κB in regulation of NKL activity.

In hen vaginal cells, NF-κB was shown to be the transcription factor responsible for the expression of various proinflammatory cytokines and chemokines. In fact, in response to the ligands of TLR3, 4, and 21, increased expression of IL1B, IL6, and CXCLi2 was observed, while IL1B expression was found in response to the ligands of TLR5 and 7 ^[53]. The authors suggested that NF-κB-dependent expression of cytokines might provide the important defense capability of vaginal tissue to bacterial and viral infections. Activation of TLR3 was shown to induce the expression of NF-κB and the production of type-I interferon ^[54]. IFN-κ (a type I IFN) in both chicken and duck was found to be constitutively expressed in a range of tissues, including spleen, skin, lung, and peripheral blood mononuclear cells (PBMCs), and it could be induced after treatment with virus in PBMCs ^[55]. The duck TLR4 (duTLR4) gene was shown to be strongly expressed in the liver, kidney, spleen, intestine, and brain ^[56].

Goose TLR3 was shown to be analogous to mammalian TLR3 and recognized double-stranded RNA with subsequent activation of NF-κB ^[54]. In fact, the goose TLR3 gene was shown to encode a protein containing 896 amino acids, sharing 46.7–84.4% homology with other species with highest expression in the pancreas and lowest in the skin. The authors showed that geese infected with H5N1 were characterized by significant upregulation of TLR3 in various tissues, including the lung and brain ^[54]. The goose TLR5 (gTLR5) gene was shown to be expressed in all studied tissues, including high expression in the liver, spleen, and brain, moderate expression in kidney, lung, heart, bone marrow, small intestine, large intestine, and PBMCs, and minimal expression in the cecum ^[57]. It was also shown that gTLR5 can detect flagellin from Salmonella Typhimurium with subsequent NF-κB activation in HEK293 cells. It seems likely that there is a tissue-specific regulation of TLR expression in the process of orchestrating the immune response against bacterial pathogens ^[57]. Goose TLR2-1 was also shown to play an important role in the recognition of Mycoplasma fermentans lipopeptide, Mycoplasma gallisepticum (MG) and Salmonella enteritidis (SE), and it induced the activation of NF-κB ^[58]. Furthermore, in HEK293T cells, flagellin was shown to induce pigeon NF-κB via TLR5 activation. This was associated with significant upregulation of IL-1β, IL-8, TNF-α, and IFN-γ. Importantly, the levels of TLR5, NF-κB, IL-6, IL-8, chemokine ligand 5 (CCL5), and IFN-γ mRNA were significantly upregulated as a result of flagellin stimulation of pigeon splenic lymphocytes. As could be expected, goose TLR5 knockdown was shown to be associated with the significantly downregulated expression of NF-κB and related cytokines/chemokines ^[59]. Interestingly, the antiviral activity of pigeon IFN-α is believed to depend on the expression of NF-κB ^[60]. It is known that single-stranded viral RNAs and antiviral imidazoquinoline compounds can be recognized by TLR7 with subsequent NF-κB activation. Recently, it was shown that, in pigeon, agonist R848 (imidazoquinoline) can activate NF-κB via TLR7 ^[61].

It seems likely that chicken NOD1 activation in response to pathogenic invasion is of great importance for immune defense. In partridge chicken, NOD1 was shown to be widely distributed in various tissues, with the highest expression found in testes. Of note, as a result of S. enterica serovar Enteritidis infection, induced expression of chNOD1, as well as the effector molecule NF-κB, was observed in the spleen tissue ^[62]. Duck NOD1 (duNOD1) was shown to be widely distributed in various organs, including heart, liver, spleen, lung, kidney, cerebrum, cerebellum, colon, glandular stomach, thymus, and bursa of Fabricius tissue with the highest expression found in the liver. Of note, duNOD1 overexpression induced NF-κB, TNF-α, and IL-6 activation in duck embryo fibroblasts (DEFs), while silencing duNOD1 was indicated to decrease the activity of NF-κB in stimulated DEFs ^[63].

Chicken IL-26 was shown to regulate immune responses through the NF-κB and the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) Janus kinase signaling pathways ^[64]. Similarly, chicken IL-11 was shown to bind to IL-11R and activated the NF-κB, JAK/STAT, and MAPK signaling pathways, leading to modulation of T helper 1 (Th1)/Th17 and Th2 cytokine production in chicken cell lines ^[65]. Chicken interleukin-17B was shown to induce the NF-κB signaling pathway, leading to increased expression of proinflammatory cytokines playing a critical role in host defense against the bacterial pathogens ^[66]. In eukaryotic and prokaryotic expression systems, recombinant chicken TNF-α was generated to demonstrate its biological activity. In particular, as a result of binding to TNF-α receptor 1, the cytokine was shown to induce a complex signaling cascade leading to induction of the classical NF-κB pathway ^[67].

In Gaoyou duck skeletal muscle (Anas platyrhynchos domesticus), NF-κB motifs (binding sites) were identified, which are believed to be responsible for transcriptional regulation of the slow skeletal muscle troponin I (TNNI1) gene ^[68]. It seems likely that chicken NF-κB plays a central role in antiviral defense. In fact, chicken tracheal epithelial cells were shown to initiate effective antiviral responses after stimulation with TLR ligands as a result of interferon regulatory factor 7 (IRF7) and NF-κB signaling pathways associated with activation of other cells, such as macrophages ^[69].

Receptor activator of NF-κB ligand (RANKL), a new member of the chicken TNF superfamily, was recently identified and characterized ^[46]. Therefore, chicken RANKL (chRANKL), sharing ~59–62% identity with mammalian RANKL, was shown to be ubiquitously expressed in chicken tissues. In nonlymphoid tissues, chRANKL mRNA expression levels were shown to be highest in muscle, while, in lymphoid tissues, the highest RANKL expression was found to be in the thymus, followed by the upper gut and the bone marrow ^[70]. Recently identified and functionally characterized chicken leukocyte immunoglobulin-like receptor A5 (LILRA5) was reported to activate/induce NF-κB, as well as other immunoregulatory pathways ^[71].

3. Effect of Various Stress Factors on NF-κB Expression and Activity in Poultry

3.1. Thermal Stress

Continuous exposure of farm animals to an acute or gradual rise in habitat temperature was shown to induce oxidative stress leading to reduced survivability and longevity ^[72], reduced growth, decreased productive and reproductive performance, and compromised health in poultry ^[73]^[74]. Intestinal damages due to thermal stress could lead to redox balance disturbances and inflammatory reactions regulated via NF-κB ^[12]. It seems likely that NF-κB expression in thermally stressed birds is condition-dependent, including temperature, exposure duration, and bird’s age. On the one hand, when quails at the age of 20 weeks were heat-stressed (34 °C for 4 h per day for 20 consecutive days), liver IL-1β and TLR4 mRNA levels were significantly increased, while NF-κB mRNA levels were significantly decreased in comparison to the control group birds kept in normal physiological conditions ^[75]. Contrary to the former, heat stress (32 ± 1 °C, 6 h/day for 9 weeks) in 25 week old Roman egg-laying hens was shown to be associated with increased serum inflammatory cytokine (IL-1β, IL-6, and TNF-α) response as compared to control nonstressed birds. Furthermore, heat stress was also responsible for significantly increased proliferating cell nuclear antigen (PCNA), TLR4, and NF-κB protein expression ^[76]. The authors showed the protective anti-inflammatory effects of curcumin (100 and 200 mg/kg) in the heat-stressed layers. Similarly, in black-boned chickens exposed to circular heat stress, dietary supplementation with resveratrol (400 mg per kg) was shown to improve intestinal integrity and ameliorate the mRNA overexpression of HSP70, HSP90, and NF-κB on the 6th, 10th, and 15th days of stress ^[77].

It seems likely that cold stress can also impose oxidative stress and enhance in vivo proinflammatory cytokine gene expression in chickens ^[78]. In fact, the expression of inflammatory factors (iNOS, COX-2, NF-κB, TNF-α, and prostaglandin E synthases (PTGEs) were shown to be increased in chicken heart due to cold stress ^[79]. Under cold stress in quail, the SOD activity decreased, reflecting an oxidative stress state, while the mRNA expression of NF-κB increased in the duodenum, jejunum, and ileum ^[80]. The inflammatory factors (COX-2, PTGEs, iNOS, NF-κB, and TNF-α) and Hsp70 mRNA levels were shown to be increased in quail spleen as a result of the acute and chronic cold stress (12 ± 1 °C) compared with birds in the control groups ^[81]. Increased malondialdehyde (MDA) content and upregulation in HSP27, HSP40, HSP70, NF-κB, COX-2, PTGEs, iNOS, TNF-α, and IL-4 mRNAs, as well as in protein levels of HSP40, NF-κB, and iNOS, were observed in heart due to acute cold stress (7 °C for 24 h) in broiler chickens ^[82]. Therefore, both heat and cold stress in poultry could be responsible for oxidative stress and inflammation, NF-κB proven to play crucial roles in the regulation of those processes.

3.2. Mycotoxins

Mycotoxins are considered as major nutritional stress factors in poultry production ^[1] imposing oxidative stress, immunosuppression ^[83], and low-grade inflammatory response in the chicken intestine ^[84] and compromising intestinal barrier functions ^[85]. Among feed-contaminating mycotoxins, AFB1 is considered to be the most toxic mycotoxin. A low level of AFB1 in broiler diet (74 μg/kg) was shown to increase the serum levels of MDA, TNF-α, and IFN-γ. These changes were inhibited by alpha-lipoic acid (α-LA) dietary supplementation (300 mg/kg). Interestingly, the activities of total SOD and GPx and the expression of NF-κB p65 and HO-1 were not affected by AFB1 ^[86]. In a similar experiment, an AFB1-contaminated diet (74 μg/kg) fed to chickens was associated with upregulation of the proinflammatory cytokine IL-6 and an increase in the protein expressions of both NF-κB p65 and i-NOS in the liver. Those negative effects of dietary AFB1 were shown to be inhibited by dietary alpha-lipoic acid (300 mg/kg ^[87]).

In an experiment with chicken feed contaminated with 1 mg/kg AFB1 fed from day 1 until day 28, broilers exposed to AFB1 were characterized by increased serum concentrations and mRNA expressions of TNF-α, IFN-γ, IL-1β, IL-10, and IL-6 as compared to the control group. In addition, AFB1 caused increased degradation of the IκBα protein and significantly elevated the phosphorylation of NF-κB (p65). Furthermore, AFB1 was responsible for a significant reduction in the mRNA level and protein expression of the Nrf2 gene. As a result, the mRNA expression and protein expression level of Nrf2-dependent antioxidant genes (HO-1, GPx1, NQO1, and GCLC) in the AFB1 group were shown to be significantly downregulated ^[88]. Interestingly, the authors demonstrated that most aforementioned changes in NF-κB and Nrf2-related parameters were partly alleviated by feeding grape seed proanthocyanidin extract (250 mg/kg) simultaneously with AFB1.

3.3. Mineral Dietary Excess and Heavy-Metal Contamination

3.3.1. Mn, Cu, and NF-κB

Mn excess (600–1800 mg/kg feed) was shown to be associated with upregulated mRNA expression of TNF-α, COX-2, NF-κB, iNOS, and NO content in chicken testis on the 60th and 90th days ^[89]. The inflammatory response and the mitochondrial dynamics and apoptosis under Cu (300 mg/kg for 90 days) exposure in the heart of chickens were also investigated. It was shown that Cu exposure induced NF-κB-mediated pro-inflammatory cytokines, and the mitochondrial network was suggested to be considered as the cytosolic sensor responsible for the induction of NF-κB-mediated inflammatory responses under stress conditions ^[90].

In chickens, dietary Cu excess (220 and 330 mg of Cu/kg dry matter) was shown to increase the number and area of splenic corpuscles, as well as the ratio of cortex and medulla in the thymus and bursa of Fabricius. Furthermore, excessive Cu intake was associated with decreased AO defenses, indicated by the reduced activities of SOD, CAT, and GPx and increased content of MDA. There were also increased TNF-α, IL-1, and IL-1β concentrations, upregulated mRNA levels of TNF-α, IFN-γ, IL-1, IL-1β, IL-2, iNOS, COX-2, and NF-κB, and increased protein levels of TNF-α, IFN-γ, NF-κB, and p-NF-κB in immune organs due to Cu toxicity ^[91].

3.3.2. As and NF-κB

The proinflammatory activities of As were shown in different tissues of birds, including liver, heart, brain, muscles, and kidney. For example, in birds chronically treated with As₂O₃, the expression levels of NF-κB and IL-6, IL-8, and TNF-α (critical mediators in the inflammatory response) in the liver were shown to be increased ^[92]. Indeed, As₂O₃ exposure (7.5–30 mg/kg for 90 days) led to oxidative stress, inflammatory response, and histological and ultrastructural damage, as reflected by altered levels of cardiac enzymes in chicken heart tissues. In addition, the messenger RNA levels of NF-κB and inflammatory cytokines (TNF-α, COX-2, NOS, and PTGEs) significantly increased due to As₂O₃ intoxication ^[93]. Similarly, when As₂O₃ (1.25 mg/kg body weight (BW), corresponding to 15 mg/kg feed) was added to a basal diet and fed to male Hy-line chickens (1 day old) for 4, 8, and 12 weeks, the expression of TNF-α, NF-κB, and iNOS in chicken heart was shown to be increased compared with the corresponding control group ^[94].

Arsenic (7.5, 15, or 30 mg/kg feed) was shown to increase the expression of NF-κB and proinflammatory cytokine expression in Gallus gallus brain tissues including cerebrum, cerebellum, thalamus, brainstem, and myelencephalon ^[95]. The toxic effects of arsenic trioxide (As₂O₃, 7.5–30 mg/kg for 30–90 days) in the muscular tissues (wing, thigh, and pectoral) of chickens were also investigated. The results showed that As₂O₃ caused oxidative stress as indicated by decreased activities of AO enzymes (catalase (CAT) and GPx) and increased MDA content. There was a significant upregulation of the mRNA levels of NF-κB and inflammatory cytokines (TNF-α, COX-2, iNOS, and PTGEs) and heat-shock proteins (HSPs) in muscular tissue in the As₂O₃ exposure groups ^[96]. In Hy-line chickens, As₂O₃ exposure (7.5, 15, and 30 mg/kg diet) was shown to induce oxidative stress and inflammatory-mediated nephrotoxicity. In fact, elevated nuclear migration of NF-κB and inflammation-related phenotypes were observed. They led to marked renal injury and apoptosis through a mitochondrion-dependent pathway in chicken kidneys ^[97].

3.3.3. Cu, As, and NF-κB

Oxidative stress-induced skeletal muscle injury due to Cu²⁺ (300 mg/kg feed) and/or arsenite (2.5 mg/kg BW, corresponding 30 mg/kg feed) exposure in chickens was associated with inflammation in skeletal muscles induced via the NF-κB-mediated response pathway. Indeed, the increased protein and mRNA levels of NF-κB and TNF-α in skeletal muscles and the enhanced mRNA expressions of IL-1β, IL-6, and IL-12β were indicative of proinflammatory responses occurring due to Cu and/or As exposure ^[98]. Arsenic (30 mg/kg) and/or copper (300 mg/kg for 12 weeks) were shown to induce oxidative stress, inflammation, and autophagy in chicken brains. In fact, the mRNA levels and protein expressions of inflammation markers (NF-κB, TNF-α, COX-2, and PTGEs) were shown to be significantly increased due to As and Cu exposure ^[99]. Chicken exposure to As (30 mg/kg) and/or Cu (300 mg/kg for 4.8 and 12 weeks) was shown to lead to oxidative stress, inflammatory response (an increase in expression of NF-κB and its downstream inflammation-related genes), and liver damage through mitochondrial and death receptor-dependent pathways ^[100]. Arsenic trioxide (30 mg/kg) and/or copper sulfate (300 mg/kg) were added to the chicken basal diet for 12 weeks. Significantly reduced thymus weight and thymus index, hyperemia visible to the unaided eye, and inflammatory cell infiltration were observed. Concurrent administration of arsenic and copper significantly enhanced inflammation as indicated by increased levels of NF-κB, COX-2, iNOS, PTGEs, and proinflammatory cytokines in chicken thymus. Additionally, oxidative stress imposed by As and Cu was associated with elevation of the heat-shock protein levels ^[101].

Increased NF-κB expression and inflammation induction in chicken gizzard were also shown to be a result of As₂O₃ and/or CuSO₄ dietary exposure ^[102]. Similarly, As and/or Cu exposure in the same doses was shown to induce immunotoxicity through triggering oxidative stress, inflammation (upregulation of NF-κB, inflammatory mediators, and proinflammation cytokines, accompanied by depletion of anti-inflammatory cytokines), and immune imbalance (decreased ratio of IFN-γ/IL-4 and increased level of IL-17) in the bursa of Fabricius of chicken ^[103]. In the chronic poisoning of Cu and/or As, inflammation occurs in the chicken thalamus as indicated by increased NF-κB expression, causing oxidative stress (MDA accumulation) and mitochondrial damage, leading to apoptosis ^[104]. Excessive intake of As (1.25 mg/kg BW) and/or Cu (CuSO4, 300 mg/kg feed) for 12 weeks was shown to lead to a significant reduction in the total antioxidant capacity (T-AOC), catalase level, and hydroxyl radical formation in chicken brain. In addition, an increase in the expression of HSPs and NF-κB, as well as NF-κB pathway-related proinflammatory mediators (COX-2, TNF-α, and iNOS), due to As/Cu intoxication was observed ^[105]. Therefore, the proinflammatory activities of Cu and As combinations were confirmed in the chicken liver, thymus, bursa of Fabricius, gizzard, thalamus, and brain.

4. Nutritional Modulation of NF-κB in Poultry

4.1. Selenium

There is a great body of evidence indicating that the micronutrient selenium (Se) and selenoproteins are involved in the regulation of inflammatory signaling pathways, including NF-κB signaling, implicated in the pathogenesis of various diseases ^[13]^[106]. As a part of 25 selenoproteins, Se is involved in antioxidant defenses and the maintenance of redox balance ^[13].

The literature data related to the effect of Se on NF-κB and inflammation can be divided into three groups. Firstly, the detrimental effects of Se deficiency or excess on NF-κB signaling were shown. Secondly, the protective effects of Se in Pb and Cd toxicity were described. Thirdly, in LPS-induced models of oxidative stress and inflammation, Se was shown to be protective.

4.1.1. Se Deficiency

Se deficiency in chickens was shown to lead to activation of the NF-κB pathway, with a change in selenoprotein gene expression resulting in kidney dysfunction ^[107]. Furthermore, Se deficiency was reported to attenuate chicken duodenal mucosal immunity via activation of the NF-κB signaling pathway. In particular, Se deficiency enhanced the phosphorylation of IκB-α and phosphorylation of kappa-B kinase subunit alpha (IKKα), as well as increased p50 and p65 DNA-binding activities. Furthermore, in Se deficiency, IKKα was elevated, but IκB-α was decreased ^[108]. The increasing levels of ROS in chicken duodenal mucosa due to Se deficiency could trigger NF-κB signal transduction ^[109]. In a recent experiment, the control group was fed a complete formula feed (0.2 mg Se/kg), while the experimental group of chickens was fed a self-made low-Se diet (0.004 mg/kg) for 15, 25, 35, 45, and 55 days. In chicken spleen at 15–45 days, the relative expression of TLR4 mRNA was shown to be increased due to Se deficiency. The relative expression of NF-κB mRNA in the experimental group was also increased in comparison to that in the control group at 15–45 days. The relative expression of IL-6 mRNA and the protein expression level of TLR4 in the experimental group were increased due to Se deficiency at 15–45 days of age ^[110]. The authors concluded that Se deficiency is associated with inflammatory injury as a result of the TLR4/TIR-domain-containing adapter-inducing interferon-β (TRIF)/NF-κB signaling pathway activation in chicken spleen.

Interestingly, the adverse effects of Se excess/toxicity (15 mg/kg Se for 45 days) on inflammatory and immune responses in chicken spleens were also associated with enhancement of the expression of NF-κB, iNOS, COX-2, PTGE, IL-6, TNF-α, and IL-4, but a depression of FOXP3 and IFN-γ ^[111]. However, Se dietary supplementation at 2 mg/kg did not affect the mRNA levels of NF-κB, COX-2, PTGEs, and TNF-α in chicken kidneys.

4.1.2. Se and Pb Toxicity

Dietary Se has been proven to alleviate the Pb-induced increase in NF-κB and HSP expression in chicken livers ^[112]. Importantly, Se supplementation (1 mg/kg diet) was shown to reduce Pb concentration in serum, partly mitigated the effect on the activation of the NF-κB pathway, and further enhanced selenoprotein expression induced by Pb exposure ^[113]. One week old male chickens were treated via drinking water with Pb (350 mg/L) and provided with dietary Se (1 mg/kg) or both Pb and Se. On the 4th, 8th, and 12th weeks, kidneys were used to assess oxidative stress indicators, relative expressions of cytokines, and other inflammatory factors. The results showed that Pb consumption imposed renal injuries associated with increased lipid peroxidation (MDA), as well as the content and expression of IL-1β, IL-6, IL-17, NLRP3, caspase-1, NF-κB, COX-2, TNF-α, and PTGEs, and with reduced GSH content, as well as GPx and SOD activities, in the chicken kidneys. Se administration was shown to alleviate the aforementioned changes ^[114].

Pb treatment (50 mg/kg for 90 days) was shown to compromise AO defenses by inhibiting the activities of SOD, GPx, and CAT, causing the accumulation of NO and MDA, leading to oxidative stress, which promoted the expression of MAPK/NF-κB pathway genes (ERK, JNK, P38, NF-κB, and TNF-α) and activated HSPs (HSP27, HSP40, HSP60, HSP70, and HSP90) in chicken spleen. However, Pb-caused necroptosis was inhibited by Se (2 mg/kg) co-treatment ^[115]. Selenium (sodium selenite, 1 μM) was shown to prevent lead (30 μM)-induced necroptosis by restoring antioxidant functions (SOD, GPx, CAT) and blocking the MAPK/NF-κB pathway (decreasing the expression of NF-κB and TNF-α) in chicken lymphocytes ^[116].

4.1.3. Se and Cd Toxicity

Dietary Cd (150 mg/kg for 90 days) was shown to increase the mRNA levels of NF-κB, COX-2, PTGEs, and TNF-α in chicken kidney. Interestingly, Se partly ameliorated the proinflammatory effects of Cd dietary supplementation ^[117]. Similarly, treatment with Se (2 mg/kg for 90 days) significantly alleviated Cd-induced hepatic toxicity (150 mg/kg) in laying hens, as evidenced by a reduction in Hsp60, Hsp70, Hsp90, NF-κB, COX-2, PTGEs, TNF-α, and IL-1β expression ^[118].

Chicken Cd exposure (150 mg/kg) was shown to activate inflammation-related genes including TNF-α, NF-κB, iNOS, COX-2, and prostaglandin E synthase (PTGEs) in chicken breast muscles ^[119]^[120]. Interestingly, Se (2 mg/kg as sodium selenite for 90 days) was reported to alleviate Cd-induced inflammation and meat quality deterioration via antioxidant and anti-inflammation action ^[120]. Supplementation with Se-yeast (0.5 mg/kg) was shown to have an antagonistic effect on Cd-induced inflammatory injury in chicken livers ^[121].

4.1.4. Se and LPS

By inhibiting the phosphorylation of NF-κB, Se was shown to reduce breast tissue inflammatory injury induced by LPS ^[122]. In laying hens, LPS stimulation (injected LPS into the abdominal cavity at the age of 8 months) imposed oxidative stress, indicated by decreased activity of SOD, GPx, and CAT, decreased GSH content, and increased H₂O₂ and MDA content in the chicken myocardium. LPS also increased the expression of p38 MAPK and NF-κB, as well as TNF-α, IL-1, PTGE, COX-2, and iNOS. Interestingly, the addition of dietary SeMet (0.5 mg/kg for 4 months) was found to alleviate the changes in the above inflammation indicators ^[123]. Similarly, SeMet (0.5 mg/kg) was shown to inhibit the LPS-induced inflammation of liver tissue via suppressing the TLR4–NF-κB–NLRP3 signaling pathway in chickens ^[124].

In a recent experiment with 46 week old ISA laying hens, birds were injected with LPS (200 mg/kg) intraperitoneally, and, after 5 h, the tracheal tissue was collected for various assays. In the LPS-treated group, the epithelial cells were shown to be degenerated with necrotic changes accompanied by inflammation. The expression of the NF-κB pathway and related inflammatory factors, including TNF-α, iNOS, NF-κB, COX-2, and PTGEs, was significantly increased in the trachea tissue due to LPS treatment. In such conditions, increased (from 0.2 up to 0.5 mg/kg) SeMet supplementation for 90 days showed anti-inflammatory effects ^[125].

4.2. Amino Acids

Dietary l-arginine supplementation (1.05–1.9%) was shown to attenuate the LPS-induced inflammatory response in broiler chickens, as evidenced by the decreased expression of IL-1β, TLR4, and PPAR-γ mRNA in the spleen, and IL-1β, IL-10, TLR4, and NF-κB mRNA in the cecal tonsils ^[126]. There were no significant interactions between immune stress caused by bovine serum albumin (BSA) and supplementation of threonine (0.49–0.76% for 21 days) for NF-κB gene expression in the jejunum or ileum of Pekin ducks ^[127].

Interestingly, NF-κB expression in the jejunum was twofold higher than that in the ileum. Leucine was reported to alleviate LPS-induced inflammatory responses as a result of downregulating the NF-κB signaling pathway. In particular, a model system employing the intestinal tissue from specific pathogen-free chick embryos cultured in the presence of LPS for 2 h was used. LPS was shown to increase the phosphorylation of NF-κB while decreasing the phosphorylation level of mTOR. In this system, leucine supplementation at 40 mM was reported to suppress the phosphorylation levels of NF-κB, while restoring the phosphorylation level of mTOR ^[128].

4.3. Phytogenic Supplements

Recently, various phytogenic supplements received tremendous attention in poultry and animal nutrition, and the molecular mechanisms of their protective actions in many cases were related to their antioxidant properties. However, researchers' analysis of the current data in this area showed that polyphenolic compounds are poorly absorbed and their concentrations in target tissues are several orders lower than those used in in vitro studies ^[129]. Furthermore, their antioxidant properties are condition-dependent, and, in many cases, polyphenols could show pro-oxidant activities. Therefore, it was suggested that the polyphenolic effects on NF-κB and Nrf2 expression could be a major molecular mechanism of their protective action in various model systems and in poultry nutrition in general ^[129]^[130]. Data presented in Section 4 showing the activation effects of polyphenol compounds on Nrf2 expression and activity with simultaneous suppression of the NF-κB pathway confirmed that idea. There are also a range of publications showing protective effects of phytogenic supplements in poultry nutrition under various stress conditions.

In chickens receiving conventional vaccinations, the NF-κB gene mRNA relative expression in hepatocytes linearly decreased as a result of increasing resveratrol, a plant-derived polyphenolic compound, with a dietary concentration from 200 to 800 mg/kg of diet ^[131]. Similarly, dietary resveratrol (200–600 mg/kg) was shown to reduce the protein expression of NF-κB, HSP70, and HSP90 in the jejunal chicken villi after 15 days of heat stress ^[77]. Dietary resveratrol (400 mg/kg) was also shown to protect quail hepatocytes against heat stress by decreasing the expression of NF-κB, Hsp70, and Hsp90, and increasing the hepatic and SOD, CAT, and GSH-Px activities ^[132]. Daidzein (DA), a soy isoflavone, included into the breeder diet at 20 mg/kg was shown to activate the NF-κB, MAPK, and Toll-like receptor signaling pathways of the offspring broilers. Furthermore, DA promoted lymphocyte development and differentiation and downregulated the expression of genes regulating lymphocyte apoptosis. It also increased the proportion of B cells, leading to promotion of Ig secretion with increased serum IgA and IgG levels and serum ND virus antibody titers ^[133]. In healthy Arbor Acre broilers, quercetin supplementation (0.04% and 0.06% for 6 weeks) was shown to significantly increase the expression of TNF-α, TNF receptor associated factor-2 (TRAF-2), TNF receptor superfamily member 1B (TNFRSF1B), nuclear factor kappa-B p65 subunit (NF-κBp65), and interferon-γ (IFN-γ) mRNA, while expression of NF-κB inhibitor-alpha (IκB-α) mRNA was significantly decreased ^[134]. Ginsenosides, the major constituents of ginseng with unique biological activities, were shown to promote proliferation of chicken primordial germ cells through protein kinase C (PKC)-involved activation of NF-κB ^[135].

Tanshinone IIA (TIIA), a major lipophilic component extracted from the root of Salvia miltiorrhiza Bunge used in Chinese medicine, was shown to have a protective effect against pulmonary arterial hypertension-related inflammatory responses ^[136]. Treatment with an extract of Hypericum perforatum L., also known as Saint John’s wort, at doses of 480–120 mg/kg for 5 days was shown to reduce infectious bronchitis virus (IBV)-induced injury and reduced the mRNA expression level of IBV in the chicken trachea in vivo. In particular, the expression of IL-6, TNF-α, and NF-κB was shown to be significantly decreased, but mitochondrial antiviral signaling gene, IFN-α, and IFN-β mRNA levels were shown to be significantly induced in vitro and in vivo ^[137].

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