Interleukins (ILs) are a group of signaling molecules that play a crucial role in the immune response, inflammation, and tissue repair processes, including wound healing. The wound-healing process begins with inflammation, during which immune cells are recruited to the wound site. Interleukins, such as IL-1, IL-6, and IL-8, play a significant role in initiating and regulating the inflammatory response. These cytokines promote the migration of immune cells to the wound site and help in removing debris and pathogens. These interleukins might influence the recruitment of immune cells to the mesh site and contribute to the breakdown of the mesh material. The mesh material itself can trigger an immune response, leading to the secretion of various interleukins and other cytokines. The presence of these interleukins can influence the recruitment of immune cells, the proliferation of fibroblasts, and the remodeling of tissue around the mesh. Proper modulation of interleukin activity is essential to ensure that the healing process occurs without excessive inflammation or fibrosis.

2. Role of Interleukins in Wound Healing

IL-2 in humans is translated as a 153-amino-acid precursor, then processed to a 15.5 kD, 133-amino-acid long, four-α-helix bundle glycoprotein ^[1][34]. IL-2 is a cytokine involved in the signaling pathways associated with the immune system, plays essential roles in several key functions of the immune system, and interacts with multiple cytokines to modulate the generation and activation of immune cells, which may also impact wound healing. IL-2 is majorly produced by CD8+ and CD4+ T-cells in an active state ^[2][35]. IL-2 mediates its action by binding to a specific receptor (IL-2R), a heterotrimeric protein expressed on the surface of certain immune cells, such as lymphocytes ^[1][34]. The IL-2 signal can be transduced through three signaling pathways: JAK-STAT, PI3K/Akt/mTOR, and MAPK/ERK ^[3][36]. It induces activation-induced cell death (AICD) and prevents autoimmune diseases by promoting the differentiation of immature T-cells into regulatory T-cells ^[4][30]. It plays a vital role in the differentiation of naive CD8+ T-cells into effector and memory T-cells, thus improving immunity ^[5][37], stimulating the differentiation of naïve CD4+ T-cells into T helper cells (Th-cells), and enhancing the cytotoxic activity of both natural killer cells and cytotoxic T-cells ^[5][6][37,38]. IL-2 production by T-cells is promoted by fibroblast growth factors (FGFs)-1 or -2, which are crucial for wound healing and angiogenesis ^[7][39]. IL-2 may be a crucial factor in the growth of fibroblasts via autophagy or through wound components derived from damaged wound organelles being digested and reallocated ^[8][40]. IL-2 stimulates the maturation of (Interferon-γ) IFN-γ-producing TH1 cells, thus augmenting the release process of IFN-γ, which leads to the production of IL-1 and helps in the wound-healing process ^[9][41].

IL-2 levels correlate positively with the percentage of burn wounds ^[10][42], act locally and not systemically, and reduced IL-2 levels are preferable at certain stages of the burn healing process ^[11][43]. In accordance with these, lower levels of IL-2 were observed at the sites of bone fractures ^[12][44], along with changes in the phosphorylation of certain proteins of the downstream IL-2 signaling pathways ^[13][45]. Wounds receiving IL-2 treatment demonstrated increased hydroxyproline, indicating increased collagen fiber cross-linking and enhanced ECM deposition ^[14][46]. On the contrary, low IL-2 levels and slow action of IL-2-regulated collagen fibers cross-linking in cell proliferation may enhance the wound closure quality ^[15][16][47,48]. Research has reported IL-2 signaling alterations to impact disease pathology that implicates tissue and skin damage, like systemic lupus erythematosus, diabetes mellitus, sarcoidosis, and myocardial infarction ^[17][49].

IL-6 acts as a pro-inflammatory, pleiomorphic cytokine, and anti-inflammatory myokine ^[18][50]. It is encoded by the IL6 gene located on chromosome 7 in humans ^[19][51]. Though IL-6 usually occurs as a 212-amino acid-long ^[20][52], 26-kD glycoprotein, its isoforms purified from various tissues have different molecular weights ranging from 19- to 70-kD due to alternate splicing of the IL-6gene and tissue-specific, post-translational modifications like phosphorylation and glycosylation ^[21][22][23][53,54,55]. IL-6 is produced by almost every cell and tissue type in humans in response to a wide variety of stimulating factors; however, several compounds also inhibit its expression ^[23][55]. IL-6 expresses its pleiotropic effects by binding to a specific receptor complex (IL-6R) located either on the membrane of the target cell (mIL-6R) through the “classical pathway” or to the soluble IL-6R (sIL-6R) through the“trans-signalling” pathway; this receptor complex consists of two transmembrane domains: CD126, a ligand binding α-chain, and CD130 or gp130, a signal-transducing β-chain ^[21][22][23][53,54,55]. The binding of IL-6 to the receptor complex results in either (i) the activation of gp130, which in turn leads to activation of the JAK/STAT/SOCS pathway, or (ii) the activation of the tyrosine phosphatase, SHP2, which in turn activates the RAS/RAF/MEK/MAPK/SOCS pathway ^[23][24][25][55,56,57]. IL-6 plays a major role in various cell functions: plasma cell development, B-cell differentiation, T-cell proliferation, maturation of cytotoxic T-cells, Ig class switching, hepatic acute phase response, inducing the synthesis of serum amyloid A and C-reactive protein, thrombopoiesis, antimicrobial activity of monocytes and neutrophils, maintenance of bodyweight, and protection against mortality in endotoxin-mediated shock and toxic shock syndrome ^[24][56].

IL-6 levels are elevated in the inflammatory and proliferative stages of wound healing, during which it involves multiple functions but returns to normal levels in the remodeling stage ^[26][58]. IL-6 plays a pivotal role in inducing acute inflammation and is, therefore, necessary for the timely activation of the process ^[27][28][59,60]. IL-6, on being released very early in response to injury, induces the chemotaxis of leukocytes into the wound and the differentiation of macrophages, B-cells, and T-cells, stimulates the growth of keratinocytes, the release of other pro-inflammatory cytokines from macrophages, keratinocytes, endothelial cells, and stromal cells residing in the wounded tissue, inhibition of proliferation of fibroblasts, induction of acute-phase protein synthesis, simulation of hematopoiesis and angiogenesis, and the release of adrenocorticotropic hormone ^{[29][30][31][32]}[61,62,63,64].

IL-6 plays an intrinsic role in the acute-phase wound response, may modulate local and systemic post-injury events by being the most persistent cytokine to mediate post-injury complications; and is robustly correlated with adverse clinical events and outcomes after mechanical trauma, burn injury, and elective surgery ^[23][55]. On wounding, elevated levels of IL-6 were detected within 24 h of bacterial infection during the initial inflammatory phase, which gradually diminished by the eighth day ^[33][65]. IL-6 was the only pro-inflammatory cytokine, the levels of which were persistently elevated post-burn injury; IL-6 levels in the serum peaked during the first few hours after injury and correlated directly with the area of the burn injury, the magnitude of the trauma, the duration of surgery, and the risk of postoperative complications ^[34][66]. IL-6 activity in human wound fluids was observed to peak within eight hours of surgery and return to baseline by the third day, a temporal pattern that may suppress the proliferation of fibroblasts in later stages ^[35][67]. IL-6 levels in the serum enhanced significantly after either laparoscopic or open IH surgery, more prominently in the latter ^[21][53], were highest on day one and fell sharply after the third day ^[36][68]. The equilibrium between pro-inflammatory cytokines like IL-6 may induce the transition from the inflammation to the proliferation phase, thus improving the healing process in skin wounds ^[37][69]. For instance, in liver transplants for treating chronic liver diseases, IL-6 engages in early graft regeneration and enhances the growth of hepatic tissue by inducing the hepatocyte stem cells to regenerate the liver parenchyma ^[38][39][70,71].

Higher IL-6 levels were observed more in non-healing wounds than in healing wounds ^[40][8], during the inflammatory phase in skin wounds in humans ^[41][72], and in both the inflammatory and granulating phases in venous leg ulcers ^[42][73]. Elevated levels of IL-6 observed in diabetic patients with foot ulcers than those without them indicate that it may play a role in their pathogenesis and development ^[42][73]. IL-6 promotes fibrosis due to an improper tissue healing process ^[26][58], stimulates the chemo-attraction of neutrophils and mitogenic activity of keratinocytes, which is linked to scar formation ^[40][8], and synergistically with hyaluronic acid affects the migration of keratinocytes through the activation of the ERK and NF-kB signalling pathway ^[43][74]. Reduced IL-6 synthesis can provide an environment conducive to scarless wound healing, as seen in the lack of inflammation observed in the fetal stages ^[44][75].