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    • IL had marked effects on the inflammatory response

    2022-01-13

    IL-33 had marked effects on the inflammatory response in human adipocytes beyond GPR84, with a substantial stimulation of the expression of a selected group of cytokine and chemokine genes. Expression of IL1B, a co-member of the IL-1 superfamily, was strongly up-regulated by IL-33, as was IL6 and CXCL2 (encoding MCP-1) and CSF3. Stimulation of MCP-1, and IL-6 from the stromovascular fraction of murine adipose tissue by IL-33 has been noted previously [13]. Stimulation of CSF3 expression was particularly marked in the present study, and this was accompanied by a major increase in the secretion of G-CSF into the medium. CSF3 expression is also strongly up-regulated in human adipocytes by IL-1β [14]. The substantial increase in G-CSF production may be linked to neutrophil recruitment and function in adipose tissue, as well as a potential neutrophic/neuroprotective role in inflammation in the tissue. In contrast to the other adipokine genes examined, IL-33 had no effect on the expression of ADIPOQ. Since adiponectin, the adipocyte hormone encoded by ADIPOQ, has anti-inflammatory and insulin sensitising functions [see 7], IL-33 does not compromise the production of a factor with these actions, unlike IL-1β and TNFα which inhibit ADIPOQ expression [7], [14]. As with GPR120, the possibility cannot be excluded of some small response to IL-33 at time-points intermediate to 3 and 24 h. There are multiple potential sources of IL-33 within adipose tissue, since the IL33 gene is expressed in adipocytes, macrophages and endothelial Betulinic Acid [12]. As such, the cytokine may have both autocrine and paracrine actions in the tissue. IL33 expression is elevated in adipose tissue of obese humans where it is suggested that it may contribute to inflammation in obesity [12], However, a protective effect of IL-3 has also been proposed [13], [16]; IL-33 reduces the inflammatory response in adipose tissue in obese mice through polarising macrophages to the M2 phenotype as well as reversing the overall recruitment of macrophages and the accumulation of pro-inflammatory cytokines [13], [16]. These changes may counter the direct pro-inflammatory effects of IL-33 on adipocytes.
    Fibrosis is characterized by the excessive accumulation of extracellular matrix in damaged or inflamed tissues, and it is the common pathological outcome of many inflammatory and metabolic diseases. Numerous clinical conditions can lead to organ fibrosis and functional failure; in many disorders, acute or persistent inflammation is crucial to trigger the fibrotic response. The production of various profibrotic cytokines and growth factors by innate inflammatory cells results in the recruitment and activation of extracellular matrix–producing myofibroblasts. There is currently a great need for therapies that could effectively target pathophysiological pathways involved in fibrosis. Free fatty acids (FFAs) are essential nutrients that exert various biological effects and have been implicated in many diseases, playing protective or harmful roles depending on the context. Besides their effects on intracellular metabolism and nuclear receptors, studies in the past 15 years have shown that FFAs can activate several cell surface G protein–coupled receptors, including FFA receptor 1 (GPR40) and GPR84. GPR40 and GPR84 show distinct characteristics in both fatty acid binding and biological effects. GPR40 is activated by both medium-chain FFAs (eg, decanoic acid) and long-chain FFAs (eg, linoleic acid), and is coupled to G or G proteins. GPR84 is responsive to medium-chain FFAs only and activates almost exclusively pertussis toxin–sensitive G signaling pathways. In addition, GPR40 and GPR84 exhibit distinct tissue distribution profiles. GPR40 is abundantly expressed in pancreatic β cells, where it enhances glucose-mediated insulin secretion. Accordingly, several GPR40 agonists have advanced to clinical trials for type 2 diabetes. However, the actions of GPR40 may not be limited to insulin secretion. GPR40 is also expressed in enteroendocrine cells of the gastrointestinal tract and may mediate release of glucagon-like peptide-1 and cholecystokinin secretion., In addition, GPR40 is expressed in murine skin and may serve to limit and attenuate inflammation. Recent studies have also involved GPR40 in regulation of pain perception and sensing taste of fatty acids. Finally, GPR40 has been shown to be expressed in the rat kidney and in a subset of murine kidney tubules, including the cortical collecting duct. Moreover, in human renal proximal tubule epithelial HK-2 cells, activation of GPR40 with the synthetic agonist GW9508 reduced cisplatin-induced apoptosis.