IL-17 produced by Paneth cells drives TNF-induced shock.
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.
Takahashi
Nozomi
N
Rheumatology Research and Advanced Therapeutics, Radboud University Nijmegen Medical Centre, 6500 HB Nijmegen, Netherlands.
Vanlaere
Ineke
I
de Rycke
Riet
R
Cauwels
Anje
A
Joosten
Leo A B
LA
Lubberts
Erik
E
van den Berg
Wim B
WB
Libert
Claude
C
D000818:Animals; D000906:Antibodies / Q000008:administration & dosage; D018836:Inflammation Mediators / Q000378:metabolism; D020381:Interleukin-17 / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D015850:Interleukin-6 / Q000097:blood; D007583:Jejunum / Q000187:drug effects / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009500:Neutralization Tests; D009569:Nitric Oxide / Q000097:blood; D019879:Paneth Cells / Q000187:drug effects* / Q000473:pathology / Q000502:physiology*; D011817:Rabbits; D053722:Receptors, Interleukin-17 / Q000172:deficiency / Q000235:genetics; D011994:Recombinant Proteins / Q000633:toxicity; D012769:Shock / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control; D018746:Systemic Inflammatory Response Syndrome / Q000209:etiology / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control; D014409:Tumor Necrosis Factor-alpha / Q000633:toxicity*
D000906:Antibodies; D018836:Inflammation Mediators; D020381:Interleukin-17; D015850:Interleukin-6; D053722:Receptors, Interleukin-17; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide