Role of IFN regulatory factor-1 and IL-12 in immunological resistance to pathogenesis of N-methyl-N-nitrosourea-induced T lymphoma.
IFN regulatory factor-1 (IRF-1) is a critical effector molecule in IFN signaling and acts as a tumor suppressor and tumor susceptibility gene. IL-12 is a key factor in the induction of innate resistance and generation of Th1 cells and CTL. Our recent study has revealed an intimate relationship between IRF-1 and IL-12 in that IRF-1 regulates the production of IL-12 by selectively controlling transcriptional activation of IL-12 p35 gene. In this work, we find that IRF-1-deficient mice are highly susceptible to N-methyl-N-nitrosourea (MNU)-induced T lymphomas. This susceptibility is associated with strong defects in the expression of IL-12, lymphotoxin (LT)beta, and IFN-gamma. Consistently, IL-12 p35(-/-), IFN-gamma(-/-), and LTbeta(-/-) mice are also highly vulnerable to MNU-induced carcinogenesis. Administration of rIL-12 to IRF-1(-/-) mice restores normal expression of LTbeta and IFN-gamma, and significantly enhances the ability of IRF-1(-/-) mice to resist MNU-induced pathogenesis. This strongly suggests an IRF-1/IL-12/IFN-gamma regulatory axis in tumor surveillance. By DNA microarray analysis, we comprehensively identify differences and patterns in gene expression in splenocytes of wild-type (WT) vs IRF-1(-/-) mice challenged with MNU. This study contributes to efforts to elucidate the cellular/molecular mechanisms and the downstream players involved in IRF-1-mediated host defense against lymphoproliferative malignancies.
Liu
Jianguo
J
Department of Microbiology and Immunology, Weill Medical College, Cornell University, 1300 York Avenue, New York, NY 10021, USA.
Xiang
Zhaoying
Z
Ma
Xiaojing
X
D000477:Alkylating Agents / Q000494:pharmacology; D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D020022:Genetic Predisposition to Disease; D050856:Interferon Regulatory Factor-1; D007371:Interferon-gamma / Q000378:metabolism; D018664:Interleukin-12 / Q000378:metabolism*; D008223:Lymphoma / Q000139:chemically induced / Q000276:immunology* / Q000378:metabolism; D008233:Lymphotoxin-alpha / Q000378:metabolism; D053308:Lymphotoxin-beta; D008565:Membrane Proteins / Q000378:metabolism; D008770:Methylnitrosourea / Q000494:pharmacology; D051379:Mice; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*
D000477:Alkylating Agents; D004268:DNA-Binding Proteins; D050856:Interferon Regulatory Factor-1; C494258:Irf1 protein, mouse; C505887:Ltb protein, mouse; D008233:Lymphotoxin-alpha; D053308:Lymphotoxin-beta; D008565:Membrane Proteins; D010750:Phosphoproteins; D018664:Interleukin-12; D008770:Methylnitrosourea; D007371:Interferon-gamma