Role of cytokines in the early stages of chronic colitis in TCR alpha-mutant mice.

Chronic colitis develops spontaneously in mice mutant for T-cell receptor alpha (TCR alpha) genes maintained in pathogen-free conditions. Our previous studies indicate that the cytokine imbalance caused by a lack of TCR alpha beta + T cells may be associated with the development of chronic colitis in TCR alpha-mutant (TCR alpha -/-) mice. The histologic changes of chronic colitis are recognizable by 3 to 4 months of age and are characterized by marked crypt cell hyperplasia and the presence of an inflammatory cell infiltrate. Because early events in the development of chronic colitis may be important in the pathogenesis of the disorder, we investigated the changes in the colon at a time when chronic colitis was not yet histologically recognizable. In vivo labeling with 5-bromo-2'-deoxyuridine revealed increased epithelial proliferation in the crypts by 6 to 8 weeks of age. There was an increase in number of T cells in the colon of TCR alpha -/- mice compared with that in TCR alpha +/- (heterozygous TCR alpha-mutant) mice after 6 weeks of age. The predominant T-cell subsets were CD4+, TCR alpha- beta +, and TCR gamma delta + cells. Reverse transcription-PCR and immunohistochemistry of the colonic mucosa obtained from TCR alpha -/- mice (> 6 weeks old) showed a marked increase of IL-1 alpha and IL-1 beta but not of TNF alpha or transforming growth factor beta-1 compared with TCR alpha +/- mice. In vivo neutralization of IL-1 alpha or IL-1 beta by specific mAb suppressed colonic epithelial proliferation and decreased colonic mucosal T-cell infiltration in 8-week-old TCR alpha -/- mice. These results provide direct evidence that overproduction of IL-1 alpha and IL-1 beta in the colonic mucosa may play an important role in the early stages of development of chronic colitis in TCR alpha -/- mice.