Combinatorial effects of interleukin 10 and interleukin 4 determine the progression of hepatic inflammation following murine enteric parasitic infection.
Mice lacking the immunoregulatory cytokine interleukin 10 (IL-10) develop necrotizing hepatitis after infection with Trichinella spiralis, and inflammation is dependent on the migration of intestinally activated CD4(+) T cells into the liver. Hepatic production of IL-4 is elevated in these mice, and we hypothesized that it plays a role in the development of hepatic pathology. Wild-type (WT), IL-10 knockout (KO), IL-4 KO, and IL-10/IL-4 KO mice were orally infected, and disease progression was followed by histological examination, alanine aminotransferase assays, and flow cytometric analysis of hepatocellular content. Both IL-10 KO and IL-10/IL-4 KO mice experienced hepatocellular injury, but only IL-10 KO mice advanced to a necrotic phase. Hepatic CD4(+) T cells were the major source of IL-4, and IL-10 regulated the number of intestinally-derived CD4(+)IL-4(+) cells. Sequestration of activated neutrophils in the liver required IL-4, and neutrophil depletion prevented progression to overt necrosis. Adoptive transfer of intestinal WT CD4(+) T cells inhibited neutrophil accumulation and inflammation, but their regulatory effects did not require IL-10 signaling.


CONCLUSIONS
The absence of IL-10 led to hepatocyte injury during infection, but IL-4 was necessary for the development of neutrophil-dependent necrosis. These studies provide new insight into the combinatorial role of these cytokines and their targets in the generation and progression of hepatic inflammation.
Baker Institute for Animal Health, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853-6401, USA.
Diana B
DB
Douglas
Daniel P
DP
Beiting
John P
JP
Loftus
Judith A
JA
Appleton
Susan K
SK
Bliss
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D004751:Enteritis / Q000150:complications / Q000378:metabolism* / Q000469:parasitology; D004804:Eosinophils / Q000502:physiology; D006505:Hepatitis / Q000209:etiology / Q000378:metabolism*; D016753:Interleukin-10 / Q000378:metabolism*; D015847:Interleukin-4 / Q000378:metabolism*; D008099:Liver / Q000276:immunology / Q000378:metabolism* / Q000469:parasitology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D014235:Trichinellosis / Q000150:complications / Q000378:metabolism*
D016753:Interleukin-10; D015847:Interleukin-4