IL-17-induced NF-κB Activation via CIKS/Act1

Abstract

Interleukin-17 (IL-17) is essential in host defense against extracellular bacteria and fungi, especially at mucosal sites, but it also contributes significantly to inflammatory and autoimmune disease pathologies. Binding of IL-17 to its receptor leads to recruitment of adaptor protein CIKS/Act1 via heterotypic association of their respective SEFIR domains and activation of transcription factor NF-B; it is not known whether CIKS and/or NF-B are required for all gene induction events. Here we report that CIKS is essential for all IL-17-induced immediate-early genes in primary mouse embryo fibroblasts, whereas NF-B is profoundly involved. We also identify a novel subdomain in the N terminus of CIKS that is essential for IL-17-mediated NF-B activation. This domain is both necessary and sufficient for interaction between CIKS and TRAF6, an adaptor required for NF-B activation. The ability of decoy peptides to block this interaction may provide a new therapeutic strategy for intervention in IL-17-driven autoimmune and inflammatory diseases.

MCPIP1 Endoribonuclease Activity Negatively Regulates Interleukin-17-Mediated Signaling and Inflammation

“…MCPIP1 was originally discovered as a target of MCP-1 and is upregulated by many inflammatory stimuli (Dhamija et al, 2013; Sonder et al, 2011). IL-17 regulates Zc3h12a through Act1-mediated activation of NF-κB and IKKγ as well as through mRNA stabilization (Somma et al, 2015; Sonder et al, 2011).…”

“…MCPIP1 was originally discovered as a target of MCP-1 and is upregulated by many inflammatory stimuli (Dhamija et al, 2013; Sonder et al, 2011). IL-17 regulates Zc3h12a through Act1-mediated activation of NF-κB and IKKγ as well as through mRNA stabilization (Somma et al, 2015; Sonder et al, 2011). MCPIP1 belongs to a family of CCCH zinc finger proteins that exhibit RNase activity against inflammatory and viral mRNA transcripts (Uehata and Akira, 2013; Xu et al, 2012).…”

“…Zc3h12a (encoding MCPIP1; also known as Regnase-1) was identified in a screen of IL-17RA-dependent genes involved in antifungal immunity (Conti et al, 2009). This gene is also induced in fibroblasts or macrophages treated with IL-17 (Dhamija et al, 2013; Sonder et al, 2011). MCPIP1 is expressed at low levels in most cell types, but is upregulated by inflammatory stimuli such as MCP-1, IL-1β and TLR ligands (Jura et al, 2012).…”

Th17 Differentiation and Their Pro-inflammation Function

“…A mimicking decoy peptide of Act1 CC' loop inhibited IL-17 induced inflammatory responses [158]. Though the SEFIR domain is important for IL-17A signaling transduction and inflammatory gene production, other studies also found that, beside to SEFIR domain, the C-terminal region and "TIR-like loop" (TILL) motif of IL-17RA, the cytoplasmic tail region of IL-17RC and the N-terminal domain of Act1, were also critical for IL-17A-mediated signaling [98,170,208,248].…”

Interleukin 17 Family Cytokines: Signaling Mechanisms, Biological Activities, and Therapeutic Implications

“…Correspondingly, Tnip1 -deficient mice develop cutaneous inflammation with psoriasiform characteristics, linking findings in this mouse model to the enhanced susceptibility to psoriasis of individuals with TNIP1 SNPs [96]. Finally, the endoribonuclease MCPIP1 (also known as Regnase-1, encoded by ZC3H12A ) limits IL-17 signaling through the degradation of IL-17-driven genes, including Il6 , Nfkbiz and Il17ra and Il17rc [97–99]. To date, 11 non-synonymous SNPs have been described for the ZC3H12A gene, but so far none are associated with human disease [100].…”