A role for the cytoplasmic adaptor protein Act1 in mediating IL-17 signaling.
Interleukin (IL)-17 (also known as IL-17A) plays an important role in host defense and inflammatory disorders, in part by linking the activation of a subset of T lymphocytes to the mobilization of neutrophils and macrophages. IL-17 exerts its effects both directly and indirectly; the latter by stimulating the production of various chemokines, IL-6, and growth factors from resident cells in the affected tissue. As a result, IL-17 coordinates the innate immune response to extracellular bacteria, which is interesting because IL-17 is produced by several types of T cells that are traditionally regarded as key players in adaptive immunity. Studies have uncovered the function and relevance of a unique subset of CD4(+) T helper (Th) cells that produce IL-17 (Th17 cells), but our understanding of the function of IL-17 receptors (IL-17Rs) and their downstream signaling pathways remains poor. This Review discusses studies that suggest that the cytoplasmic adaptor protein Act1 [nuclear factor-kappaB (NF-kappaB) activator 1] is essential for linking stimulation of IL-17Rs to downstream signaling pathways, and, therefore, that Act1 might play a role in local inflammatory responses. Act1 mediates activation of NF-kappaB and the subsequent production of IL-6 and chemokines that are chemotactic for neutrophils and macrophages. These findings have increased our understanding of host defense against bacteria and indicated a role for Act1 in mediating in chronic inflammatory disease. Future studies on Act1 and IL-17 signaling should contribute to the identification and improved understanding of the mechanisms behind aberrant innate immune responses in chronic inflammatory disease.
Department of Internal Medicine/Respiratory Medicine and Allergology, Institute of Medicine, Sahlgrenska Academy at Göteborg University, Sweden. anders.linden@gu.se
Anders
A
Lindén
D048868:Adaptor Proteins, Signal Transducing / Q000276:immunology* / Q000378:metabolism; D000818:Animals; D003593:Cytoplasm / Q000378:metabolism; D006801:Humans; D020381:Interleukin-17 / Q000276:immunology*; D015850:Interleukin-6 / Q000378:metabolism; D018448:Models, Immunological; D016328:NF-kappa B / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology*
D048868:Adaptor Proteins, Signal Transducing; D020381:Interleukin-17; D015850:Interleukin-6; D016328:NF-kappa B