*3.3. IL-6*

The IL-6 family of cytokines include IL-6, IL-11, IL-27, IL-31, oncostatin M, leukaemia inhibitory factor, ciliary neurotrophic factor, cardiotrophin 1, and cardiotrophin- like cytokine factor 1 [112]. They play crucial roles in cell proliferation, survival, migration, invasion, and inflammation [113].

## 3.3.1. The Source of IL-6

IL-6 is mainly produced by lymphocytes, myeloid cells, fibroblasts and epithelial cells [114]. Enterocyte IL-6 production is increased during inflammatory conditions such as sepsis and endotoxemia [115].

## 3.3.2. The Function of IL-6

IL-6 and its soluble receptor s-IL6R are highly elevated in the colonic mucosa of IBD [116]. The single nucleotide polymorphism rs2228145 in IL-6R associates with increased levels of s-IL6R, as well as reduced IL-6R signaling and risk of IBD [117]. A randomized clinic trial in 36 patients with active CD showed that 80% of the patients given a human anti-IL-6R monoclonal antibody biweekly at a dose of 8 mg/kg had a clinical response compared with only 31% of placebo injected patients, indicating that targeting IL-6 signaling may serve as a promising strategy for CD [118].

IL-6 promotes IEC proliferation and regeneration, and IL6-deficient mice exhibit elevated IEC apoptosis following exposure with DSS [119]. The proliferative and antiapoptotic effects of IL-6 are mainly mediated by the transcription factor STAT3, whose IEC-specific ablation leads to more severe DSS-induced colitis compared to wild-type mice [98]. In addition, the IL-6 co-receptor gp130 stimulates intestinal epithelial cell proliferation through Yes-associated protein (YAP) and Notch signaling, which leads to aberrant differentiation and promotion of mucosal regeneration [120]. Activation of YAP [121] and Notch [122] are required for mucosal regeneration after DSS challenge.

## 3.3.3. The Regulation of IL-6

IL-6 is a multifunctional NF-kB-regulated cytokine that acts on epithelial and immune cells [119]. Endotoxin and IL1-β stimulates IL-6 production from IEC [123]. IFN-γ alone did not stimulate but synergistically potentiated the effect of IL-1β stimulated IL-6 production [124]. In contrast, TGF-β and cAMP were found to enhance IL-6 secretion, and they could potentiate IL-1β stimulated IL-6 production [125,126]. All four major transcription factors, i.e., NF-B, activator protein-1, CCAAT/enhancer binding protein, and CREB, are involved in the cAMP activated IL-6 production [126].
