Revisiting the role of IL-27 in obesity-related metabolic diseases: safeguard or perturbation?

Abstract

The prevalence of metabolic diseases, such as obesity, has been steadily increasing in recent years, posing a significant threat to public health. Therefore, early identification and intervention play a crucial role. With the deepening understanding of the etiology of metabolic diseases, novel therapeutic targets are emerging for the treatment of obesity, lipid metabolism disorders, cardiovascular and cerebrovascular diseases, glucose metabolism disorders, and other related metabolic conditions. IL-27, as a multi-potent cytokine, holds great promise as a potential candidate target in this regard. This article provides a comprehensive review of the latest findings on IL-27 expression and signal transduction in the regulation of immune inflammatory cells, as well as its implications in obesity and other related metabolic diseases. Furthermore, it explores the potential of IL-27 as a novel therapeutic target for the treatment of obesity and metabolic disorders. Finally, an overview is presented on both the opportunities and challenges associated with targeting IL-27 for therapeutic interventions.

Keywords: a new target; abnormal glucose metabolism; cardiovascular diseases; il-27; immune inflammation; lipid metabolism disorder; metabolic diseases; obesity.

Figure 1

Schematic diagram of some immune cells regulated by IL-27. The secretion of IL-27 can be observed in various immune cells, including dendritic cells, monocytes, macrophages, plasma cells, and natural killer cells. IL-27 is a heterodimeric cytokine consisting of two subunits: EBI-3 and P28. The receptor for IL-27 is composed of WSX-1 (IL-27Rα) and gp130. Upon receptor activation, it exerts regulatory effects on downstream immune cells through JAK/STATs, MAPK pathways, as well as other signaling cascades that remain to be elucidated. IL-27 is a unique bidirectional regulator of inflammation, exerting a broad and significant regulatory role in diverse immune cell populations. It has the ability to activate STAT3, inhibit Fas-mediated apoptosis of CD4⁺T cells, and promote the expansion of CD4⁺T cells. Additionally, IL-27 facilitates the differentiation of Th0 cells into Th1 while suppressing their differentiation into Th2 by inhibiting GATA-3 expression through the STAT1 pathway. Moreover, IL-27 can impede the differentiation of Th0 cells into Th17 via activation of the STAT1 pathway. The stimulation of IL-27 can induce B cells to secrete T-bet and IgG2a, while inhibiting the secretion of IgG1 by B cells through STAT1 signaling. The expression of T-bet and GzmB in NK cells was promoted by IL-27 via the STAT1/3 pathway, thereby augmenting the functionality of NK cells through stimulation of IFN-γ secretion mediated by the STAT1 signal. The activation of STAT1/2/3/4/5 signaling in CD8⁺T cells by IL-27 leads to the direct release of Prf and GzmB, enabling the killing of tumor cells. The activation of STAT1 in macrophages by IL-27 leads to the augmentation of TLR-induced reduction in IL-10 and inflammation. Simultaneously, it attenuates the impact of TNF-α on human macrophages, thereby exerting an anti-inflammatory effect through a feedback mechanism. The expression of TLR4 in monocytes can be enhanced by IL-27 through the activation of STAT3/NF-κB signaling pathway, leading to the upregulation of downstream IL-6 and TNF-α expression. The expression of programmed death-related factor B7-H1 in DC can be up-regulated by IL-27, thereby inhibiting its function in promoting T cell proliferation.

Figure 2

Part of IL-27 signaling pathways in obesity and other related metabolic diseases. IL-27 can promote the expression of thermogenic factor UCP1 by activating the p38MAPK-PGC-1α signaling pathway, depleting energy, reducing lipid accumulation, and inhibiting the occurrence of obesity. IL-27 can inhibit the activation of APC and T lymphocytes, reduce inflammatory factors, and inhibit the occurrence of diabetes. However, IL-27 can also affect the differentiation balance of CD4⁺ T lymphocytes, increase the maturation of Th1 pro-inflammatory cells, and promote the accumulation of CD8⁺ T lymphocytes, which can destroy islet β cells and promote the occurrence of diabetes. IL-27 can activate the JAK2/STAT3 signaling pathway in monocyte-macrophages, up-regulate the expression of ABCA1 protein, reduce the number of foam cells, and inhibit atherosclerosis. IL-27 can also activate STAT3 signaling pathway, reduce cellular reactive oxygen species level, reduce myocardial cell damage, and inhibit atherosclerosis. IL-27 can inhibit the excessive activation of CD4⁺ T lymphocytes, Th17 cells and chemokines, thereby inhibiting renal tubulointerstitial fibrosis and preventing the occurrence of secondary hypertension. IL-27 can activate STAT3 signaling pathway, reduce the levels of inflammatory molecules TNF-α and IL-1β, and increase the secretion of anti-inflammatory factor IL-10, thereby reducing the degree of nerve cell damage and the volume of cerebral infarction. IL-27 can activate STAT3-mTOR signaling, promote the synthesis and secretion of intestinal GLP-1, and alleviate IR. IL-27 can activate CD4⁺ and CD8⁺ cells in the intestinal intraepithelial lymphocyte population to provide an immune barrier to the intestine, and inhibit the differentiation of Th17 cells to reduce intestinal inflammation.