Differential requirement for NF-kappa B family members in control of helminth infection and intestinal inflammation.
The NF-kappaB family of transcription factors is critical in controlling the expression of a wide range of immune response genes. However, whether individual family members perform specific roles in regulating immunity and inflammation remains unclear. Here we investigated the requirement for NF-kappaB1, NF-kappaB2, and c-Rel in the expression of Th2 cytokine responses, development of host protective immunity, and regulation of intestinal inflammation following infection with the gut-dwelling helminth parasite Trichuris muris. While mice deficient in c-Rel mounted sufficient Th2 responses to expel infection, NF-kappaB1 knockout (KO) and NF-kappaB2 KO mice developed chronic infections associated with elevated production of Ag-specific IFN-gamma. However, only infected NF-kappaB1 KO mice exhibited polarized IFN-gamma responses associated with the loss of intestinal goblet cells and the development of destructive colitis-like pathology. Furthermore, blockade of IL-12 (previously shown to confer resistance in susceptible strains) recovered Ag-specific IL-13 responses and resistance to infection in NF-kappaB2 KO, but not NF-kappaB1 KO mice. Therefore, unique infection, immunological, and pathological outcomes were observed in different NF-kappaB KO strains. Taken together, these results provide direct evidence of nonoverlapping functions for NF-kappaB family members in the development of Th2 cytokine-mediated resistance to T. muris and the control of infection-induced intestinal inflammation.
Artis
David
D
Department of Pathobiology, University of Pennsylvania School of Veterinary Medicine, 3800 Spruce Street, Philadelphia, PA 19104, USA. dartis@vet.upenn.edu
Shapira
Sagi
S
Mason
Nicola
N
Speirs
Kendra M
KM
Goldschmidt
Michael
M
Caamaño
Jorge
J
Liou
Hsiou-Chi
HC
Hunter
Christopher A
CA
Scott
Phillip
P
D000818:Animals; D002478:Cells, Cultured; D002908:Chronic Disease; D003092:Colitis / Q000235:genetics / Q000276:immunology / Q000473:pathology; D016207:Cytokines / Q000096:biosynthesis; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D007113:Immunity, Innate / Q000235:genetics; D018664:Interleukin-12 / Q000037:antagonists & inhibitors / Q000502:physiology; D018793:Interleukin-13 / Q000096:biosynthesis; D007411:Intestinal Diseases, Parasitic / Q000235:genetics / Q000276:immunology* / Q000469:parasitology / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D005810:Multigene Family / Q000276:immunology; D016328:NF-kappa B / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D052002:NF-kappa B p50 Subunit; D052003:NF-kappa B p52 Subunit; D020569:Proto-Oncogene Proteins c-rel / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D014257:Trichuriasis / Q000235:genetics / Q000276:immunology* / Q000469:parasitology / Q000473:pathology*; D014258:Trichuris / Q000276:immunology*
D016207:Cytokines; D018984:Epitopes, T-Lymphocyte; D018793:Interleukin-13; D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; D052003:NF-kappa B p52 Subunit; D020569:Proto-Oncogene Proteins c-rel; D018664:Interleukin-12