IL-17 produced by Paneth cells drives TNF-induced shock
Open Access
- 28 July 2008
- journal article
- Published by Rockefeller University Press in The Journal of Experimental Medicine
- Vol. 205 (8), 1755-1761
- https://doi.org/10.1084/jem.20080588
Abstract
Tumor necrosis factor (TNF) has very potent antitumor activity, but it also provokes a systemic inflammatory response syndrome that leads to shock, organ failure, and death. Here, we demonstrate that interleukin (IL)-17, a proinflammatory cytokine known to be produced mainly by activated T cells, has a critical role in this process. Antiserum against IL-17 or deletion of Il17r protected mice against a lethal TNF challenge. Serum levels of TNF-induced IL-6 and nitric oxide metabolites were significantly reduced in mice deficient in the IL-17R. TNF-induced leukocyte influx in the small intestine was reduced, and there was no injury to the small intestine. Surprisingly, electron microscopy showed that IL-17 was constitutively present in Paneth cells of the crypts. Upon TNF challenge, the intracellular pool of IL-17 in these cells was drastically reduced, suggesting rapid release of IL-17 from the granules of Paneth cells. Our findings assign a novel role for IL-17 in an acute inflammation and identify Paneth cells as a source of the IL-17 that plays a role in this process. These data indicate that innate immune cytokine responses in the local mucosa may participate in rapidly amplifying responses to systemic inflammatory challenges.Keywords
This publication has 31 references indexed in Scilit:
- T cell self-reactivity forms a cytokine milieu for spontaneous development of IL-17+ Th cells that cause autoimmune arthritisThe Journal of Experimental Medicine, 2007
- Critical role of IL-17 receptor signaling in acute TNBS-induced colitisInflammatory Bowel Diseases, 2006
- A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17Nature Immunology, 2005
- Interleukin 17–producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineagesNature Immunology, 2005
- IL-23 drives a pathogenic T cell population that induces autoimmune inflammationThe Journal of Experimental Medicine, 2005
- Interleukin-17 Family Members and InflammationImmunity, 2004
- Antigen-Specific T Cell Sensitization Is Impaired in IL-17-Deficient Mice, Causing Suppression of Allergic Cellular and Humoral ResponsesImmunity, 2002
- HSP70 Protects against TNF-Induced Lethal Inflammatory ShockImmunity, 2002
- Protection against TNF-Induced Lethal Shock by Soluble Guanylate Cyclase Inhibition Requires Functional Inducible Nitric Oxide SynthaseImmunity, 2000
- Tumor necrosis factors: developments during the last decade.1996