Critical role of IL-1α in IL-1β-induced inflammatory responses: Cooperation with NF-κBp65 in transcriptional regulation

Abstract

The IL-1 cytokines are considered among the first family of cytokines that orchestrate acute and chronic inflammatory diseases. Both IL-1β and IL-1α are members of the IL-1 family; however, their distinct roles in the inflammatory processes remain poorly understood.Weexplored the role of IL-1α in IL-1β-activated signaling pathways causing synovial inflammation inrheumatoid arthritis (RA).Usingsynovial fibroblasts isolated fromRAjoints,wefound that IL-1β significantly stimulated IL-1α expression, which was selectively inhibited by blocking the NF-κB pathway. Knockdown of IL-1α using small interfering RNA abolished IL-1β-induced pro-IL-1α and pro-IL-1β expression and suppressed inflammation. Native and chromatin immunoprecipitation studies showed that IL-1α cooperates in NFkBp65 binding to the distal region of IL-1α promoter and to the proximal region of IL-1β promoter upstream of the transcription start site to stabilize their gene transcription. Molecular dynamics simulation of IL-1α or IL-1β binding to IL-1 receptor showed distinct interaction sites that corroborate with the ability of IL-1α to differentially activate phosphorylation of signaling proteins compared with IL-1β. Our study highlights the importance of IL-1α in mediating IL-1β-induced inflammation in addition to maintaining its expression and providing a rationale for targeting IL-1α to minimizethe roleof IL-1β in inflammatory diseases likeRA.