Pro-Inflammatory and Anti-Inflammatory Interleukins in Infectious Diseases

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1		Ahmed Al-Qahtani	--	1937	2024-01-22 10:40:39	\|
2	format change	Peter Tang	Meta information modification	1937	2024-01-23 04:33:39	\|

This entry is adapted from the peer-reviewed paper 10.3390/tropicalmed9010013

Interleukins (ILs) are signaling molecules that are crucial in regulating immune responses during infectious diseases. Pro-inflammatory ILs contribute to the activation and recruitment of immune cells, whereas anti-inflammatory ILs help to suppress excessive inflammation and promote tissue repair.

interleukins infectious diseases pro-inflammatory anti-inflammatory immune response diagnosis therapy

1. Introduction

Infectious diseases remain a major public health concern, causing significant morbidity, and continue to be a significant public health issue globally ^[1]. These diseases are caused by disease-causing microorganisms like viruses, bacteria, fungi, and parasites, which can enter the body through various means, such as ingestion, inhalation, or contact with contaminated surfaces or bodily fluids. Entry of infectious pathogens into the host causes the immune system to activate a complex defense mechanism involving the activation of various immune cells as well as the production of different signaling molecules, including cytokines. Interleukins are a type of cytokine that plays a crucial role in modulating the immune response to infectious agents. Interleukins are produced by different immune cells such as B cells, T cells, dendritic cells, and macrophages. These immune molecules act on different target cells, including immune cells, endothelial cells, and epithelial cells. Several interleukins are involved in the immune response to infectious agents, and these can be classified as either pro-inflammatory or anti-inflammatory depending on their effects on the immune system.

Pro-inflammatory interleukins, such as interleukin-1β (IL-1β) and IL-6, are essential for initiating the immune response to infectious agents. They stimulate immune cell recruitment and activation, increase their vascular permeability, and induce fever, all of which are critical for fighting off invading pathogens. However, excessive secretion of pro-inflammatory interleukins can lead to a hyper-inflammatory response, which can cause tissue damage and contribute to the development of severe infections and sepsis ^[2]^[3]^[4].

In contrast, anti-inflammatory interleukins, such as IL-10 and transforming growth factor-beta (TGF-β), play an important role in limiting inflammation and preventing tissue damage ^[5]^[6]. They inhibit the production of pro-inflammatory cytokines and promote differentiation and activation of regulatory immune cells, which can help to control the immune response and promote tissue repair ^[7]^[8]. However, an excessive anti-inflammatory response can also be detrimental, as it can lead to immune suppression and impaired pathogen clearance.

Interleukins can significantly influence the immune response and vaccine efficacy. For instance, interleukins like IL-2 or IL-15 are used to stimulate the immune system, enhancing the activation and proliferation of immune cells when incorporated into vaccine formulations ^[9]. In addition, interleukins often serve as adjuvants, substances added to vaccines to boost their effectiveness. For example, IL-33 has been found to improve CD8+ T cell response during chronic infection while its incorporation as a vaccine adjuvant was found to enhance humoral response in a DNA-based human immunodeficiency virus (HIV) vaccine ^[10]^[11]. Thus, by improving the body’s immune memory and promoting a stronger and longer-long-lasting response, interleukins may contribute to more potent vaccines. Furthermore, interleukins are critical in shaping the balance between Th1 and Th2 immune responses, which is crucial for generating the appropriate type of immunity needed for a particular vaccine ^[12]. Vaccines targeting intracellular pathogens may require a Th1-biased response, while those against extracellular pathogens may necessitate a Th2-biased response. Here, interleukins help fine-tune this balance to optimize vaccine outcomes.

Interleukins also influence the development of memory T cells, which are essential for long-term immunity. This underscores the pivotal role that interleukins play in shaping the adaptive immune response. Memory T cells are a specialized subset of T lymphocytes that recognize previous encounters with pathogens, allowing the immune system to respond more rapidly and effectively upon re-exposure. Interleukins, such as IL-7 and IL-15, are critical in promoting the formation and maintenance of memory T cells by supporting the survival, proliferation, and differentiation of these cells ^[13]^[14]. Memory T cells are crucial for sustaining immunity over time due to their protection against recurring infections, including viral infections like influenza and bacterial infections like tetanus ^[15]^[16]. Understanding the influence of interleukins on immune cell development is not only fundamental to our comprehension of immune response but also holds significance in drug design for infectious diseases to ensure sustained protection against infectious diseases.

2. Pro-Inflammatory Interleukins

Pro-inflammatory interleukins are cytokines that are produced in response to infectious agents and other inflammatory stimuli (Table 1).

Table 1. Pro-inflammatory Cytokines in Infectious Diseases.

Cytokine	Cell Source	Function in Infectious Disease	Associated Diseases	Reference
Interleukin-1β	Macrophages, monocytes	Induces fever, activates immune response	Sepsis, septic shock, bacterial and viral infections	^[2]^[7]
Interleukin-6	Macrophages, T cells, fibroblasts	Facilitates immune response, promotes inflammation	Sepsis, pneumonia, viral infections	^[11]^[12]
Interleukin-12	Dendritic cells, macrophages	Enhances cellular immune response	Intracellular infections (e.g., tuberculosis)	^[13]

3. Anti-Inflammatory Cytokines

Anti-inflammatory interleukins are characterized by their ability to suppress pro-inflammatory signaling pathways and dampen immune responses (Table 2). These interleukins utilize different mechanisms to inhibit inflammation and production of pro-inflammatory cytokines and regulate immune cell activation and function.

Table 2. Anti-inflammatory cytokines, mechanisms, and associated diseases.

Cytokine	Cell Source	Function in Infectious Disease	Associated Diseases	Reference
Interleukin-10	Macrophages, regulatory T cells	Downregulates immune response, suppresses inflammation	HIV infection, sepsis, and chronic infections	^[17]^[18]^[19]
Interleukin-1 Receptor Antagonist (IL-1Ra)	Various cell types	Limits IL-1-mediated inflammation	Rheumatoid arthritis, sepsis, and infectious diseases	^[9]^[20]
Interleukin-4	T cells, mast cells, and basophils	Modulates immune response, promotes antibody production	Parasitic infections, allergies	^[21]^[22]
Interleukin-13	T cells, mast cells, and basophils	Downregulates inflammation, supports tissue repair	Asthma, helminth infections	^[23]^[24]

4. Interleukins as Biomarkers of Clinical Importance

Interleukins, as biomarkers with clinical utility, hold significant promise in the early and precise diagnosis of various diseases, thus playing a crucial role in improving treatment outcomes. This is especially critical in conditions where early detection remains a formidable challenge, such as infectious disease. One of the primary functions of interleukins as biomarkers is their ability to reflect the state of the immune system. In HIV infection, for instance, the decrease in levels of interleukins like IL-2 and IL-13, alongside the elevation of pro-inflammatory cytokines including IL-1, IL-6, and IL-8, serves as a clear indicator of the immune imbalance associated with the disease ^[25]^[26]^[27]. The reduction in IL-2, an essential cytokine for immune regulation, represents an early immunological dysregulation in HIV ^[25]. This early detection of immune system alterations through interleukin profiling offers clinicians a valuable tool for identifying HIV infection at its nascent stages. Furthermore, interleukins can provide critical diagnostic thresholds for other infectious diseases. For example, the cut-off level of IL-6 at 4000 pg mL⁻¹ has been established for tuberculosis with pleural effusions, enabling a more precise diagnosis of this condition ^[28]. This cut-off level has been found to have considerable predictive and diagnostic value for tuberculosis with pleural effusions, with a sensitivity of 90.6% and specificity of 76.5%. In neonatal medicine, interleukins like IL-6, IL-8, IL-10, and IL-12 are employed as biomarkers for diagnosing conditions such as sepsis ^[29]. Their specific cut-off values provide clinicians with essential guidance in making accurate and timely diagnoses in neonates, where early intervention is vital. Interleukins also find utility in the diagnosis and management of other diseases beyond infectious ones. For instance, IL-4 upregulation detected through advanced techniques like three-color flow cytometry serves as a valuable indicator in certain clinical contexts ^[30].

5. Crosstalk between Pro-Inflammatory and Anti-Inflammatory Cytokines

The crosstalk between pro-inflammatory and anti-inflammatory interleukins is a complex and dynamic process that influences immune responses and immune homeostasis. Extensive research has shed light on the intricate interplay between these interleukins, providing insights into their regulatory mechanisms and therapeutic potential.

Pro-inflammatory interleukins, such as IL-1β, IL-6, and TNF-α, are key players in initiating and amplifying immune responses during infection or tissue injury ^[16]. They promote the activation of immune cells and the release of pro-inflammatory mediators. However, anti-inflammatory interleukins, such as IL-4, -IL-10, and IL-13, are crucial regulators that counterbalance pro-inflammatory signals and facilitate the resolution of inflammation ^[31].

One aspect of the crosstalk between pro-inflammatory and anti-inflammatory interleukins involves negative feedback loops which prevent harmful responses. Pro-inflammatory interleukins can stimulate the production of anti-inflammatory interleukins to limit excessive inflammation. For instance, high expression of IL-1β and IL-6 are linked to reduced IL-10 production and vice versa as a mechanism to suppress the pro-inflammatory response and prevent tissue damage ^[32]. As highlighted here, it is known that IL-10 acts as a potent suppressor of pro-inflammatory cytokine production by immune cells, thus attenuating immune response during infection and reducing inflammation.

In addition to negative feedback regulation, anti-inflammatory interleukins can directly inhibit the production and activity of pro-inflammatory cytokines. For example, IL-10 exerts anti-inflammatory effects by suppressing the expression of pro-inflammatory cytokines. Studies have demonstrated that IL-10 inhibits the production of IL-1β and IL-6 in various cell types, including macrophages, monocytes, and T cells ^[33]^[34]. IL-4 and IL-13 also exhibit anti-inflammatory functions and can downregulate pro-inflammatory cytokine production, particularly from T cells and macrophages ^[23]^[24].

Moreover, the crosstalk between pro-inflammatory and anti-inflammatory interleukins influences the differentiation and function of immune cell subsets. Pro-inflammatory cytokines, including IL-1β, IL-6, and TNF-α, promote the development of pro-inflammatory Th cell subsets, including Th1 and Th17, which drive inflammatory responses ^[35]^[36]. In contrast, anti-inflammatory interleukins, such as IL-4 and IL-10, play a critical role in promoting the differentiation of anti-inflammatory Th-cell subsets. IL-4 induces the development of Th2 cells, which are implicated in immune responses against parasitic infections and exhibit anti-inflammatory properties ^[37]^[38].

Current research continues to uncover the intricacies of the crosstalk between pro-inflammatory and anti-inflammatory interleukins. It highlights the importance of maintaining a delicate balance between these cytokines for proper immune regulation and prevention of excessive inflammation. Dysregulation of this balance is implicated in various diseases, including autoimmune disorders and chronic inflammatory conditions.

Understanding the crosstalk between these interleukins at a molecular level has paved the way for potential therapeutic interventions. Targeting specific interleukins or their signaling pathways holds promise for modulating immune responses and restoring immune balance in inflammatory diseases. Several studies have explored the use of IL-10-based therapies to control inflammation and ameliorate disease severity. For example, pre-clinical studies investigating the administration of IL-10 or IL-10 receptor agonists have shown promising results in inflammatory bowel disease (IBD) ^[39], where excessive pro-inflammatory cytokines play a significant role in disease pathogenesis. This is particularly relevant to infectious diseases as IBD comprises diseases like ulcerative colitis and Crohn’s disease. Ulcerative colitis and Crohn’s disease patients unfortunately have a higher risk of common infections, viral infections, and gastrointestinal infections ^[40]. These approaches aim to enhance the anti-inflammatory actions of IL-10 and restore immune homeostasis.

Furthermore, the development of biological agents targeting pro-inflammatory cytokines has provided effective therapeutic options for various inflammatory conditions. For instance, monoclonal antibodies against TNF-α, such as infliximab and adalimumab, have revolutionized the treatment of diseases like RA, psoriasis, and inflammatory bowel disease ^[41]^[42]. These agents directly neutralize TNF-α, alleviating pro-inflammatory signals and dampening immune responses.

Although there has been no research focusing on the potential of combining anti-inflammatory and pro-inflammatory cytokine-targeted therapies to achieve synergistic effects and better disease control, studies showing anti-TNF-α, for instance, result in IL-10 induction in IBD ^[43]. This may provide insight into the co-administration of IL-10 with anti-TNF-α agents in the treatment of inflammatory infectious diseases like colitis and IBD toward enhanced therapeutic outcomes, with reduced inflammation and improved tissue healing. This suggests that a comprehensive approach targeting both pro-inflammatory and anti-inflammatory pathways may offer greater efficacy in managing inflammatory diseases.

The crosstalk between pro-inflammatory and anti-inflammatory interleukins is a vital mechanism that regulates immune responses and maintains immune balance. Dysregulation of this crosstalk can facilitate the development and progression of different inflammatory diseases. Understanding the intricate interactions between these cytokines has opened avenues for targeted therapies aimed at restoring immune equilibrium. The development of IL-10-based therapies and the success of anti-cytokine biologic agents provide promising strategies for managing infectious and inflammatory diseases. Future research will continue to unravel the complexities of this crosstalk and uncover novel therapeutic approaches for immune-mediated disorders.

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