IL-10 regulates movement of intestinally derived CD4+ T cells to the liver.
Diseases that affect the intestine may have hepatic manifestations, but the mechanisms involved in establishing hepatic disease secondarily remain poorly understood. We previously reported that IL-10 knockout (KO) mice developed severe necrotizing hepatitis following oral infection with Trichinella spiralis. In this study, we used this model of intestinal inflammation to further examine the role of IL-10 in regulating hepatic injury. Hepatic damage was induced by migrating newborn larvae. By delivering the parasite directly into the portal vein, we demonstrated that an ongoing intestinal immune response was necessary for the development of hepatitis. Intestinally derived CD4+ cells increased in the livers of IL-10 KO mice, and Ab-mediated blockade of MAdCAM-1 inhibited the accumulation of CD4+alpha(4)beta(7)+ cells in the liver. Moreover, adoptive transfer of intestinally primed CD4+ T cells from IL-10 KO mice caused hepatitis in infected immunodeficient animals. Conversely, transfer of wild-type donor cells reduced the severity of hepatic inflammation in IL-10 KO recipients, demonstrating regulatory activity. Our results revealed that IL-10 prevented migration of intestinal T cells to the liver and inhibited the development of hepatitis.
Bliss
Susan K
SK
James A. Baker Institute for Animal Health, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853, USA. spk2@cornell.edu
Bliss
Stuart P
SP
Beiting
Daniel P
DP
Alcaraz
Ana
A
Appleton
Judith A
JA
D000818:Animals; D000906:Antibodies / Q000187:drug effects; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D015815:Cell Adhesion Molecules / Q000037:antagonists & inhibitors; D002465:Cell Movement; D016207:Cytokines / Q000378:metabolism; D005260:Female; D006505:Hepatitis / Q000276:immunology* / Q000469:parasitology; D039441:Integrin alpha4 / Q000032:analysis; D039641:Integrin beta Chains / Q000032:analysis; D016753:Interleukin-10 / Q000235:genetics / Q000502:physiology*; D007411:Intestinal Diseases, Parasitic / Q000276:immunology; D007422:Intestines / Q000276:immunology / Q000469:parasitology; D008099:Liver / Q000276:immunology* / Q000473:pathology; D008109:Liver Diseases, Parasitic / Q000276:immunology / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009088:Mucoproteins; D014235:Trichinellosis / Q000276:immunology
D000906:Antibodies; D015815:Cell Adhesion Molecules; D016207:Cytokines; D039641:Integrin beta Chains; C489082:Madcam1 protein, mouse; D009088:Mucoproteins; C091368:integrin beta7; D016753:Interleukin-10; D039441:Integrin alpha4