Experimental murine colitis is regulated by two genetic loci, including one on chromosome 11 that regulates IL-12 responses.
OBJECTIVE
Immunogenetic analysis of experimental colitis may contribute to the further unraveling of the complex genetic basis of the inflammatory bowel diseases, Crohn's disease and ulcerative colitis.


METHODS
Genetic regions associated with susceptibility to trinitrobenzene sulfonic acid (TNBS)-induced colitis were identified in a genome-wide linkage analysis in F2 progeny of colitis-susceptible SJL/J and -resistant C57BL/6 mice. An immunogenetic approach was then used to further study the pathophysiologic role of one of the identified loci.


RESULTS
We identified susceptibility loci on chromosomes 9 (Tnbs1) and 11 (Tnbs2). Tnbs2 harbors the interleukin (IL)-12 p40 gene, a likely candidate gene because IL-12 is a known central mediator for both experimental colitis and human Crohn's disease. We therefore tested the ability of colitis-susceptible and -resistant strains to mount IL-12 responses to lipopolysaccharide (LPS), a strong inducer of IL-12 that is abundantly present in the intestine. We observed a remarkably higher serum IL-12 response to LPS in susceptible SJL/J mice. Subsequently, we showed that the genetic region regulating the IL-12 response to LPS colocalizes with Tnbs2.


CONCLUSIONS
These data strongly suggest that the tendency to mount a high LPS-induced IL-12 response and susceptibility to TNBS-induced colitis are related and that in fact a genetically determined high IL-12 response is involved in the immunologic basis of susceptibility to colitis.
Bouma
Gerd
G
Mucosal Immunity Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
Kaushiva
Anjali
A
Strober
Warren
W
D000818:Animals; D002874:Chromosome Mapping; D003092:Colitis / Q000235:genetics* / Q000276:immunology; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D015212:Inflammatory Bowel Diseases / Q000235:genetics; D018664:Interleukin-12 / Q000096:biosynthesis* / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D012737:Sex Factors; D014302:Trinitrobenzenesulfonic Acid
D018664:Interleukin-12; D014302:Trinitrobenzenesulfonic Acid