Critical role of IL-1 in IL-1-induced inflammatory responses: cooperation with NF-Bp65 in transcriptional regulation

The IL-1 cytokines are considered among the first family of cytokines that orchestrate acute and chronic inflammatory diseases. Both IL-1 and IL-1 are members of the IL-1 family; however, their distinct roles in the inflammatory processes remain poorly understood. We explored the role of IL-1 in IL-1-activated signaling pathways causing synovial inflammation in rheumatoid arthritis (RA). Using synovial fibroblasts isolated from RA joints, we found that IL-1 significantly stimulated IL-1 expression, which was selectively inhibited by blocking the NF-B pathway. Knockdown of IL-1 using small interfering RNA abolished IL-1-induced pro-IL-1 and pro-IL-1 expression and suppressed inflammation. Native and chromatin immunoprecipitation studies showed that IL-1 cooperates in NF-Bp65 binding to the distal region of IL-1 promoter and to the proximal region of IL-1 promoter upstream of the transcription start site to stabilize their gene transcription. Molecular dynamics simulation of IL-1 or IL-1 binding to IL-1 receptor showed distinct interaction sites that corroborate with the ability of IL-1 to differentially activate phosphorylation of signaling proteins compared with IL-1. Our study highlights the importance of IL-1 in mediating IL-1-induced inflammation in addition to maintaining its expression and providing a rationale for targeting IL-1 to minimize the role of IL-1 in inflammatory diseases like RA.Singh, A. K., Fechtner, S., Chourasia, M., Sicalo, J., Ahmed, S. Critical role of IL-1 in IL-1-induced inflammatory responses: cooperation with NF-Bp65 in transcriptional regulation.