Hall of Fame among Pro-inflammatory Cytokines: Interleukin-6 Gene and Its Transcriptional Regulation Mechanisms

Abstract

Pro-inflammatory cytokines that are generated by immune system cells and mediate many kinds of immune responses are kinds of endogenous polypeptides. They are also the effectors of the autoimmune system. It is generally accepted that interleukin (IL)-4, IL-6, IL-9, IL-17, and tumor necrosis factor-α are pro-inflammatory cytokines; however, IL-6 becomes a protagonist among them since it predominately induces pro-inflammatory signaling and regulates massive cellular processes. It has been ascertained that IL-6 is associated with a large number of diseases with inflammatory background, such as anemia of chronic diseases, angiogenesis acute-phase response, bone metabolism, cartilage metabolism, and multiple cancers. Despite great progress in the relative field, the targeted regulation of IL-6 response for therapeutic benefits remains incompletely to be understood. Therefore, it is conceivable that understanding mechanisms of IL-6 from the perspective of gene regulation can better facilitate to determine the pathogenesis of the disease, providing more solid scientific basis for clinical treatment translation. In this review, we summarize the candidate genes that have been implicated in clinical target therapy from the perspective of gene transcription regulation.

Orexin A increases sympathetic nerve activity through promoting expression of proinflammatory cytokines in Sprague Dawley rats

“…AP‐1 is a transcription regulator that controls transcription of multiple genes through binding with the consensus sequence in or near their promoter regions. There are AP‐1 binding sites in the promoter regions of PICs . This evidence, coupled with the observations that (i) OX1R and Fra1 are colocalized in the PVN neurons and (ii) the maximum increase of Fra1 occurred earlier than PICs (3 hours in Fra1 and 6 hours in PICs) in response to orexin A stimulation, suggests that increased AP1 may promote transcriptions of PICs.…”

MicroRNA124-IL6R Mediates the Effect of Nicotine in Inflammatory Bowel Disease by Shifting Th1/Th2 Balance Toward Th1

“…Soluble IL-6 binds with high affinity to the IL-6Rα chain and signal-transducing βsubunit gp130, inducing homodimerization of gp130. Activation of gp130 homodimer leads to tyrosine kinase phosphorylation of the JAK family, as well as the recruitment and activation of STAT-1 and STAT-3 (47)(48)(49)(50)(51)(52)(53)(54). STAT3 plays an important role in the pathogenesis of UC (55-57).…”

Mutant glucocorticoid receptor binding elements on Interleukin-6 promoter regulate dexamethasone effects

“…The exact targeted regulation of GR2/3 on IL-6 and the possible mechanism related to transcriptional synergism with GRE remain unknown. Whether GR2/3 plays a novel negative GRE [33], directly binding by GRα, the pivotal subunit of GR, which could involve the interactions between GRα and AP-1and NF-κB, needs further studies to identify.…”