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Background & Aims: Mice with a disrupted gene for the G-protein inhibitory 2 chain (Gnai2 / ) develop a spontaneous colitis resembling human inflammatory bowel disease. Disease expression differs markedly between inbred strains of mice, indicating genetic control of disease susceptibility. We performed a genome-wide screen to localize the chromosomal regions regulating disease expression. Methods: A total of 284 F2 mice derived from resistant C57BL/6J Gnai2 / mice and susceptible C3H/HeN Gnai2 / mice were analyzed in a genome-wide screen for colitis susceptibility and severity. Results: A highly significant locus on chromosome 3 (Gpdc1) contributed to colitis susceptibility and severity (likelihood ratio statistics [LRS] 32.4; LOD score 7; P< 1.0 10 5 ). The peak linkage of this locus at 62 cM colocalizes exactly with a previously identified locus controlling colitis susceptibility in interleukin-10 – deficient mice. In addition, evidence for linkage with a locus on chromosome 1 (Gpdc2; LRS 19.7; LOD 4.3) was found, and the 2 loci interacted epistatically (combined LRS 68.2). A third locus (Gpdc3) was found on chromosome 9 and this locus interacted epistatically with a locus on chromosome 7, which by itself did not have an effect on the trait. Conclusions: The identification of a major locus on chromosome 3 that controls susceptibility to spontaneous colitis in 2 different gene-knockout models indicates that this locus harbors a gene(s) that plays a key role in maintaining mucosal homeostasis. Identification of this gene(s) may contribute to further understanding of the mechanisms underlying human inflammatory bowel disease.

‡Background & Aims: 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.

Proper adrenal glucocorticoid secretion is crucial in the course of inflammatory diseases. However, the function and structure of the adrenal glands have not been examined in inflammatory bowel diseases.After induction of trinitrobenzene sulfonic acid (TNBS) colitis in SJL/J mice, plasma hormone and cytokine levels were measured, adrenal structure was analyzed by immunohistochemistry and electron microscopy, and adrenal cytokine/cytokine receptor expression were studied by RNase protection.Adrenals of colitic animals were enlarged and hypervascularized. These animals had a marked increase in plasma corticosterone levels during the course of colitis (270 +/- 34 vs. 16 +/- 11 ng/mL; P0.0001) but only a modest elevation of their concurrent adrenocorticotropin levels (57 +/- 13 vs. 29 +/- 9 pmol/L; NS). On electron microscopy, adrenocortical cells showed ultrastructural signs of marked stimulation, and intra-adrenal lymphocytes were frequently found in direct contact with these cells. Concurrent plasma levels of interleukin (IL)-6, the major cytokine activating the hypothalamic-pituitary-adrenal axis, were markedly increased (495 +/- 131 vs. 20 +/- 1.5 pg/mL; P0.0001), and this cytokine directly stimulated corticosterone secretion by adrenocortical cells in vitro. Intra-adrenal expression of IL-6 in animals with colitis was increased 80-fold, and the IL-6 receptor subunits IL-6R alpha and gp130 were present in the adrenal cells. Treatment of animals with neutralizing anti-IL-6 antibody reduced the TNBS-induced growth and activation of the adrenal cortices.Colitis is associated with a profound stimulation of adrenocortical cell function and glucocorticoid release. Direct immune-adrenal interactions seem to contribute to this activation of the adrenal glands during colitis.

Study objective Cardiopulmonary bypass (CPB) induces a generalized inflammatory response, including activation of leukocytes, contributing to postoperative morbidity. The inflammatory pathways leading to this systemic inflammatory response syndrome are considered identical to those involved in septic shock. Therefore, we studied the release of bactericidal/permeability-increasing protein (BPI), lipopolysaccharide binding protein (LBP), and soluble CD14 (sCD14)-all proteins that modulate the effects of lipopolysaccharide (LPS)-in patients undergoing CPB. In addition, the effect of heparin coating of the extracorporeal bypass circuit on the release of these parameters was assessed. Design Prospective, randomized clinical pilot study. Setting Cardiothoracic Surgery Department in a university hospital. Patients Fourteen patients undergoing elective coronary artery bypass grafting were included. Seven patients underwent CPB using a standard, noncoated extracorporeal circuit, and seven patients had CPB using a heparin-coated extracorporeal circuit (Duraflo II). Interventions Blood samples were taken after induction of anesthesia, just before aortic crossclamping, and 0, 0.5, 1.5, 3, 6, 12, and 24 h after declamping. Measurements and results CPB with a noncoated extracorporeal circuit induced a sharp increase in neutrophil-derived BPI, manifest directly after release of the aortic crossclamp, which was significantly attenuated using a heparin-coated system. Also, CPB induced a gradual increase of the acute-phase reactant LBP, which was identical in the noncoated and heparin-coated groups. Systemic release of sCD14 after crossclamp release was significantly higher in the noncoated group compared with the heparin-coated group, but did not rise above baseline levels. Conclusions These data confirm that CPB-induced leukocyte activation is attenuated using a heparin-treated extracorporeal circuit and point to the possible role of LPS toxicity-modulating proteins in the systemic inflammatory response after bypass surgery.