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.
Douglas
Diana B
DB
Baker Institute for Animal Health, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853-6401, USA.
Beiting
Daniel P
DP
Loftus
John P
JP
Appleton
Judith A
JA
Bliss
Susan K
SK
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