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Published online before print May 14, 2007

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(Journal of Leukocyte Biology. 2007;82:237-243.)
© 2007 by Society for Leukocyte Biology

Crosstalk among Jak-STAT, Toll-like receptor, and ITAM-dependent pathways in macrophage activation

Xiaoyu Hu^*, Janice Chen, Lu Wang^* and Lionel B. Ivashkiv^*,,1

^* Arthritis and Tissue Degeneration Program, Hospital for Special Surgery, New York, New York, USA; and
Graduate Program in Immunology and Microbial Pathogenesis, Weill Graduate School of Medical Sciences of Cornell University, New York, New York, USA

¹ Correspondence: Hospital for Special Surgery, 535 East 70th Street, Research Building, Room 400, New York, NY 10021, USA. E-mail: ivashkivl{at}hss.edu

ABSTRACT

Macrophage phenotype and activation are regulated by cytokines that use the Jak-STAT signaling pathway, microbial recognition receptors that include TLRs, and immunoreceptors that signal via ITAM motifs. The amplitude and qualitative nature of macrophage activation are determined by crosstalk among these signaling pathways. Basal ITAM signaling restrains macrophage responses to TLRs and other activating ligands, whereas strong ITAM signals synergize with the same ligands to activate cells strongly. Similarly, basal ITAM signaling augments IFN signaling and function of receptor activator of NF-B, but extensive ITAM activation inhibits Jak-STAT signaling. Thus, intensity and duration of ITAM signaling determine whether ITAM-coupled receptors augment or attenuate TLR and Jak-STAT responses. IFN- synergizes with TLRs in part by suppressing TLR-induced feedback inhibition, mediated by IL-10 and Stat3, by a mechanism that depends on glycogen synthase kinase (GSK)3 regulation of AP-1 and CREB. IFN- suppresses TLR2 and TLR4 induction/activation of AP-1 by overlapping mechanisms that include regulation of MAPKs, GSK3-dependent suppression of DNA binding, and decreased Fos and Jun protein expression and stability. IFN- suppression of TLR-induced activation of AP-1 and downstream target genes challenges current concepts about the inflammatory role of AP-1 proteins in macrophage activation and is consistent with a role for AP-1 in the generation of noninflammatory osteoclasts. Jak-STAT, TLR, and ITAM pathways are basally active in macrophages and strongly induced during innate responses. Thus, signal transduction crosstalk is regulated in a dynamic manner, which differs under homeostatic and pathologic conditions, and dysregulation of signal transduction crosstalk may contribute to pathogenesis of chronic inflammatory diseases.

Key Words: cytokine • AP-1/CREB • RANK

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