Interleukin 17 (IL-17) is a highly versatile pro-inflammatory cytokine crucial for a variety of processes including host defense, tissue repair, inflammatory disease pathogenesis and cancer progression. In contrast to its profound impact in vivo, IL-17 exhibits surprisingly moderate activity in cell culture models, presenting a major knowledge gap regarding the molecular mechanisms of IL-17 signaling. Emerging studies reveal a new dimension of complexity in the IL-17 pathway that may help explain its potent and diverse in vivo functions. Discoveries of new mRNA stabilizers and receptor-directed mRNA metabolism provide insights into the means by which IL-17 cooperates functionally with other stimuli in driving inflammation, whether beneficial or destructive. Integration of IL-17 with growth receptor signaling in specific cell types offer new understanding in the mitogenic impact of IL-17 in tissue repair and cancer. This review summarizes new developments in IL-17 signaling and their pathophysiological implications.
This study identifies and characterizes for the first time the BP-haptenated peptides from HSA involved in the immunization of patients to penicillins.
Excessive cytokine activity underlies many autoimmune conditions, particularly through the interleukin-17 (IL-17) and tumor necrosis factor–α (TNFα) signaling axis. Both cytokines activate nuclear factor κB, but appropriate induction of downstream effector genes requires coordinated activation of other transcription factors, notably, CCAAT/enhancer binding proteins (C/EBPs). Here, we demonstrate the unexpected involvement of a posttranscriptional “epitranscriptomic” mRNA modification [N6-methyladenosine (m6A)] in regulating C/EBPβ and C/EBPδ in response to IL-17A, as well as IL-17F and TNFα. Prompted by the observation that C/EBPβ/δ-encoding transcripts contain m6A consensus sites, we show that Cebpd and Cebpb mRNAs are subject to m6A modification. Induction of C/EBPs is enhanced by an m6A methylase “writer” and suppressed by a demethylase “eraser.” The only m6A “reader” found to be involved in this pathway was IGF2BP2 (IMP2), and IMP2 occupancy of Cebpd and Cebpb mRNA was enhanced by m6A modification. IMP2 facilitated IL-17–mediated Cebpd mRNA stabilization and promoted translation of C/EBPβ/δ in response to IL-17A, IL-17F, and TNFα. RNA sequencing revealed transcriptome-wide IL-17–induced transcripts that are IMP2 influenced, and RNA immunoprecipitation sequencing identified the subset of mRNAs that are directly occupied by IMP2, which included Cebpb and Cebpd. Lipocalin-2 (Lcn2), a hallmark of autoimmune kidney injury, was strongly dependent on IL-17, IMP2, and C/EBPβ/δ. Imp2−/− mice were resistant to autoantibody-induced glomerulonephritis (AGN), showing impaired renal expression of C/EBPs and Lcn2. Moreover, IMP2 deletion initiated only after AGN onset ameliorated disease. Thus, posttranscriptional regulation of C/EBPs through m6A/IMP2 represents a previously unidentified paradigm of cytokine-driven autoimmune inflammation.
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