Abstract
Immunoreceptor tyrosine-based activation motif (ITAM)–coupled receptors modulate the amplitude and nature of macrophage responses to Toll-like receptor and cytokine receptor stimulation. However, the molecular mechanisms enabling this receptor crosstalk are not known. Here we investigated the function of the calcium-dependent kinases CaMK and Pyk2 'downstream' of ITAM-associated receptors in the regulation of cytokine-induced activation of Jak kinases and STAT transcription factors. CaMK and Pyk2 relayed signals from integrins and the ITAM-containing adaptor DAP12 to augment interleukin 10– and interferon-α-induced Jak activation and STAT1-dependent gene expression. CaMK inhibition suppressed STAT1-mediated interferon-α signaling in a mouse model of systemic lupus erythematosus. Our results associate Pyk2 and Jak kinases with the linkage of signals emanating from cytokine and heterologous ITAM-dependent receptors.
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Acknowledgements
We thank V. Tybulewicz (National Institute for Medical Research, London) for heterozygous Syk-deficient mice; T. Chatila (University of California at Los Angeles) for CaMKIV-deficient bone marrow; R. Silver for help with calcium flux experiments; J. Hamerman for discussions; X. Hu for critically reviewing the manuscript; and L. Kellerman, B. Bertucci and E. Barreda for technical support. Supported by the National Institutes of Health (L.B.I.; and AR 051448, AR 051886 and P50 AR 054086 to J.S.) and the Abbott Scholar Program (I.T.).
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L.W. designed and did experiments and wrote the manuscript; I.T. designed and did experiments; K.-H.P.-M. and A.C.R. did experiments; H.G.-H. did experiments and provided reagents; J.S. and R.B. provided reagents; J.J.Z. did the mouse B cell experiments; and L.B.I. designed and supervised research and wrote the manuscript.
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Wang, L., Tassiulas, I., Park-Min, KH. et al. 'Tuning' of type I interferon–induced Jak-STAT1 signaling by calcium-dependent kinases in macrophages. Nat Immunol 9, 186–193 (2008). https://doi.org/10.1038/ni1548
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DOI: https://doi.org/10.1038/ni1548
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