Inhibition of Helicobacter hepaticus-induced colitis by IL-10 requires the p50/p105 subunit of NF-kappa B.
Defects within the innate immune system sensitize NF-kappaB-deficient (p50(-/-); p65(+/-)) mice to Helicobacter hepaticus (Hh)-induced colitis. Because IL-10 plays a central role in the inhibition of Hh-induced colitis, we hypothesized that the ability of IL-10 to inhibit the innate inflammatory response to Hh may be compromised in NF-kappaB-deficient mice. To test this hypothesis, we evaluated the ability of an IL-10-Ig fusion protein with IL-10-like properties to inhibit Hh-induced colitis in RAG-2(-/-) (RAG) and p50(-/-); p65(+/-); RAG-2(-/-) (3X/RAG) mice. As expected, IL-10-Ig efficiently inhibited the development of colitis in RAG mice. In contrast, the ability of IL-10-Ig to inhibit colitis was compromised in 3X/RAG mice. The defect in response to IL-10-Ig appeared to be primarily the result of the absence of the p50/p105 subunit, because the ability of IL-10-Ig to inhibit colitis was also compromised in p50(-/-); RAG-2(-/-) (p50/RAG) mice. Radiation chimeras demonstrated that the presence of p50/p105 within hemopoietic cells of the innate immune system was necessary for efficient inhibition of colitis by IL-10-Ig. Consistent with a defect in the suppressive effects of IL-10 in the absence of p50/p105, we found that the ability of IL-10 to control LPS-induced expression of IL-12 p40 was significantly compromised in macrophages lacking p50/p105. These results suggest that the absence of the p50/p105 subunit of NF-kappaB within hemopoietic cells of the innate immune system interferes with the ability of IL-10 to suppress inflammatory gene expression and Hh-induced colitis.
Tomczak
Michal F
MF
Immunology Research Division, Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA.
Erdman
Susan E
SE
Davidson
Anne
A
Wang
Yan Yan
YY
Nambiar
Prashant R
PR
Rogers
Arlin B
AB
Rickman
Barry
B
Luchetti
David
D
Fox
James G
JG
Horwitz
Bruce H
BH
D000818:Animals; D003092:Colitis / Q000235:genetics / Q000276:immunology* / Q000382:microbiology / Q000517:prevention & control*; D003106:Colon / Q000276:immunology / Q000382:microbiology; D016481:Helicobacter Infections / Q000235:genetics / Q000276:immunology* / Q000517:prevention & control*; D044923:Helicobacter hepaticus / Q000254:growth & development / Q000276:immunology*; D006412:Hematopoietic Stem Cells / Q000276:immunology / Q000378:metabolism; D018836:Inflammation Mediators / Q000276:immunology / Q000502:physiology / Q000627:therapeutic use; D016753:Interleukin-10 / Q000172:deficiency / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D053762:Interleukin-12 Subunit p40 / Q000096:biosynthesis / Q000235:genetics; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D052002:NF-kappa B p50 Subunit / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000627:therapeutic use
D018836:Inflammation Mediators; D053762:Interleukin-12 Subunit p40; D052002:NF-kappa B p50 Subunit; D011993:Recombinant Fusion Proteins; D016753:Interleukin-10