IRAK4 kinase activity mediates IRF5 activation via IKK and TAK1

IRAK4 kinase plays a critical role in innate immune responses and inflammation by modulating the TLR/IL-1R signaling pathway, yet the mechanism by which it regulates downstream pathways and transcription factors to induce inflammatory cytokines is unclear. IRAK4 can mediate signaling events by mechanisms both dependent and independent of its kinase activity. Understanding this regulation is important for deciphering the role of IRAK4 and for the development of treatments for inflammatory diseases and cancer. Through transcriptomic and biochemical analyses of primary human monocytes treated with a highly potent and selective inhibitor of IRAK4, we show that IRAK4 kinase activity controls the transcription factor IRF5 which in turn induces inflammatory cytokine and type I interferon transcription in myeloid cells. We also show that IRAK4 kinase activity does not control activation of NF-B. Following TLR stimulation, translocation of IRF5, but not NF-B, to the nucleus in human monocytes is abolished by IRAK4 kinase inhibition. In addition, binding of IRF5, but not NF-B p65, to promoters of inflammatory target genes (TNF- and IP10) is blocked with an IRAK4 kinase inhibitor. IKK, a known activator of IRF5, is phosphorylated in response to TLR mediated signaling, and inhibition of IRAK4 kinase blocks IKK phosphorylation. Pharmacological inhibition of IKK and TAK1, the upstream kinase of IKK, in human monocytes blocks IL-1, IL-6 and TNF- cytokine production, as well as IRF5 translocation to the nucleus. Taken together, our data suggest a novel mechanism by which IRAK4 kinase activity regulates TAK1 and IKK activation, leading to the translocation of IRF5 and induction of inflammatory cytokines in human monocytes.

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Cushing L, Winkler A, Jelinsky SA, Lee K, Korver W, Hawtin R, Rao VR, Fleming M, Lin LL