The Roles of IL-1 Family Cytokines in the Pathogenesis of Systemic Sclerosis

Abstract

The IL-1 family consists of 11 cytokines, 7 ligands with agonist activity (IL-1α, IL-1β, IL-18, IL-33, IL-36α, IL-36β, IL-36γ) and four members with antagonistic activities [IL-1 receptor antagonist (IL-1Ra), IL-36Ra, IL-37, IL-38]. Recent articles have described that most members of IL-1 family cytokines are involved in the process of innate and adaptive immunity as well as fibrosis in systemic sclerosis (SSc). IL-1 family gene polymorphisms, abnormal expression of IL-1 and its potential role in the fibrosis process have been explored in SSc. IL-33 and IL-18 have also been discussed in the recent years. IL-33 may contribute to the fibrosis of SSc, while IL-18 remains to be researched to confirm its role in fibrosis process. There is a lack of study on the pathophysiological roles of IL-36, IL-37, and IL-38 in SSc, which might provide us new study area. Here, we aim to give a brief overview of IL-1 family cytokines and discuss their pivotal roles in the pathogenesis of SSc.

Keywords: IL-1 family cytokines; fibrosis; pathogenesis; scleroderma; systemic sclerosis.

Figure 1

Common signaling pathway for IL-1 family cytokines. IL-1α, IL-1β, IL-18, IL-33, and IL-36 bind to IL-1R family members, recruiting MyD88, IRAK4, TRAF6, which resulted in the activation of NF-κB and MAPK and then promoting the transcription of several inflammatory genes. IL-37 and IL-38 exert anti-inflammatory effects by inhibiting NF-κB and MAPK signaling. IL-1Ra and IL-36 Ra cannot recruit the signaling chain.

Figure 2

The pathogenic roles of IL-1 family in SSc. Key mechanisms by which IL1α, IL-1β, and IL-33 promotes a variety of cells activation and transition are summarized in a schematic form. IL-1α and IL-1β can induce fibroblast proliferation and fibrosis through promoting the production of IL-6 and PDGF. In addition, IL-1β can also promote EMT and the differentiation of Th17 cells, which both play crucial roles in SSc. IL-33 induces the expansion of Th2 cells, ILC2, and M2 macrophages to increase the production of IL-13. IL-13 is a profibrotic cytokine that is sufficient for the induction of fibrosis in SSc. PDGF, platelet-derived growth factor; EMT, epithelial-mesenchymal transition; ILC2, type 2 innate lymphoid cell.