Pathological role of large intestinal IL-12p40 for the induction of Th2-type allergic diarrhea.
IL-12 consists of two disulfide-linked subunits, p40 and p35, that form functionally active heterodimers for the induction of Th1 cells. In contrast to IL-12 heterodimers, p40 monomers and homodimers possess inhibitory effects on Th1 cells leading to the creation of a Th2 environment. Although it has been shown that IL-12p40 acts as antagonist of IL-12p70 in vitro, no evidence is currently available whether IL-12p40 is functional in vivo. We now report that IL-12p40 plays an important pathological role in anintestinal allergic disease. A high expression of IL-12p40 protein was demonstrated in epithelial cells, dendritic cells, and macrophages in large but not small intestine of allergic diarrhea-induced mice. Interestingly, neutralization with anti-IL-12p40 mAbs reduced the incidence and delayed the onset of disease development. Lower levels of ovalbumin (OVA)-specific IgE Abs in serum were detected in anti-IL-12p40 mAb-treated mice than in control Ab-treated mice. The secretion of Th2 cytokines and eotaxin by the mononuclear cells isolated from the large intestine of anti-IL-12p40 mAb-treated mice was significantly decreased. Finally, the removal of the IL-12p40 gene resulted in complete inhibition of disease development. These results show that over-expression of IL-12p40 is an important contributing factor for the generation of the dominant Th2-type environment in the large intestine of mice with allergic diarrhea.
Hino
Ayako
A
Division of Mucosal Immunology, Department of Microbiology and Immunology, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
Kweon
Mi-Na
MN
Fujihashi
Kohtaro
K
McGhee
Jerry R
JR
Kiyono
Hiroshi
H
D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology / Q000378:metabolism; D015153:Blotting, Western; D054413:Chemokine CCL11; D019742:Chemokines, CC / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000378:metabolism; D003967:Diarrhea / Q000139:chemically induced / Q000276:immunology* / Q000473:pathology*; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D004847:Epithelial Cells / Q000378:metabolism; D006967:Hypersensitivity; D007073:Immunoglobulin E / Q000097:blood; D007150:Immunohistochemistry; D018664:Interleukin-12 / Q000502:physiology*; D053762:Interleukin-12 Subunit p40; D007420:Intestine, Large / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009077:Mucins; D010047:Ovalbumin / Q000276:immunology / Q000494:pharmacology; D021122:Protein Subunits / Q000502:physiology*; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018418:Th2 Cells / Q000276:immunology*
D000951:Antigens, Neoplasm; C515457:Ccl11 protein, mouse; D054413:Chemokine CCL11; D019742:Chemokines, CC; D016207:Cytokines; D053762:Interleukin-12 Subunit p40; D009077:Mucins; D021122:Protein Subunits; D012333:RNA, Messenger; C042384:gastro-intestinal mucus-associated antigens; D018664:Interleukin-12; D007073:Immunoglobulin E; D010047:Ovalbumin