PS1-67 TYK2 is required for IL-17 production by innate immune cells in response to IPS

The Janus kinase (JAK) family member tyrosine kinase 2 (Tyk2) is an integral part of various cytokine and growth hormone signaling pathways. We have reported previously that macrophages from Tyk2-deficient mice exhibit selective defects in response to lipopolysaccharide (LPS). We demonstrate now, that LPS stimulation induces interleukin-17 (IL-17) production via a Tyk2-dependent pathway in thioglycolate-elicited peritoneal macrophages. IL-17 and IL-17F were upregulated upon LPS treatment with similar kinetics and both mRNAs were considerably reduced in the absence of Tyk2. Interestingly, signal transducer and activator of transcription 3 (STAT3) was not required for LPS-induced IL-17 production in macrophages. In the absence of STAT3, IL-17/IL-17F mRNA and IL-17 protein expression were strongly increased upon LPS treatment and, to a lower extend, produced constitutively. Thus, in contrast to its essential role in the differentiation/maintenance of IL-17 producing T cells (Th17), STAT3 exerts inhibitory rather than stimulatory effects on LPS-induced IL-17 production in macrophages. Of note, we also prove that Tyk2 is indispensable for IL-17 production following LPS challenge in vivo. We could exclude mature T cells as main source of IL-17 in spleens following intraperitoneal administration of LPS. Currently, we are investigating the contribution of Tyk2 to innate IL-17 production in specific cell types in vivo.