Interleukin-1β Mediates the Extra-Intestinal Thrombosis Associated with Experimental Colitis

Abstract

Inflammatory bowel diseases (IBDs) are associated with an increased risk for thromboembolism, which is often manifested as deep vein thrombosis or pulmonary embolism, at extra-intestinal sites. Although some of the cytokines that contribute to IBD pathogenesis are also known to alter the coagulation pathway, it remains unclear whether these mediators also contribute to the extra-intestinal thrombosis often associated with IBD. The objective of this study is to evaluate the role of interleukin (IL)-1␤ in enhanced extra-intestinal thrombosis observed in mice with dextran sodium sulfate (DSS)-induced colitis. IL-1␤ concentrations were measured in plasma, colon, and skeletal muscle of wild-type (WT) control and colitic mice. Microvascular thrombosis was induced in cremaster muscle microvessels by using a light/dye injury model. The effects of exogenous IL-1␤ on thrombus formation were determined in control WT mice. DSS-induced thrombogenesis was evaluated in WT mice treated with an IL-1␤ antibody and in IL-1 receptor-deficient (IL-1r؊/؊ ) mice. DSS-induced colonic inflammation in WT mice was associated with enhanced thrombus formation in arterioles. IL-1␤ concentrations were elevated in inflamed colon and skeletal muscle. Exogenous IL-1␤ enhanced thrombosis in control mice in a dose-dependent manner. DSS colitic mice treated with the IL-1␤ antibody as well as IL1r ؊/؊ mice exhibited significantly blunted thrombogenic responses. These findings implicate IL-1␤ as a mediator of enhanced microvascular thromboses that occur in extra-intestinal tissues during colonic inflammation.

Inflammatory Bowel Disease: Mechanisms, Redox Considerations, and Therapeutic Targets

“…Furthermore, IL-1b release and caspase-1 activity induced by DSS treatment were significantly inhibited by MAPK kinase inhibitors, and by NAC, a precursor of the antioxidant GSH (141). Extra-intestinal complications, such as thrombosis, have been related to IL-1b enhancement in mice with DSS-induced colitis (293). As discussed at length earlier, the implication of IL-1b in the pathogenesis of IBD gained new importance with the discovery of the NLRP3 inflammasome.…”

“…In this connection, synthetic antibodies against IL-1b and IL-18 have been developed, in an attempt to reduce the severity of colitis in animal models (118,235,293).…”

Ginsenoside Rd attenuates the inflammatory response via modulating p38 and JNK signaling pathways in rats with TNBS-induced relapsing colitis

“…In combination with its soluble receptor sIL-6Rα, IL-6 dictates the transition from acute to chronic inflammation by changing the nature of leucocyte infiltrate (from polymorphonuclear neutrophils to monocyte/macrophages) [38,39]. In association with IL-6, IL-1 may contribute to the constitutional symptoms of IBD and lead to the generation of acute phase proteins [40]. TNF-α exerts its proinflammatory effects through increased production of IL-1β and IL-6, expression of adhesion molecules, proliferation of fibroblasts and procoagulant factors, as well as initiation of cytotoxic, apoptotic, acute-phase responses, and inhibition of apoptosis [41,42].…”

IL-6 Mediates the Intestinal Microvascular Thrombosis Associated with Experimental Colitis

“…[3][4][5][6] A similar propensity for thrombus development at extraintestinal sites has been demonstrated in different animal models of colitis. [7][8][9][10][11] However, enhanced thrombosis within the vasculature of the inflamed bowel has not been demonstrated in these experimental models.…”

“…8,9,12 Among the cytokines, that have been implicated in human and experimental IBD, [13][14][15][16] only IL-6 exhibits the ability to mediate all of the characteristic platelet responses to colonic inflammation, including thrombocytosis, platelet hyper-reactivity, and accelerated thrombus formation. [15][16][17][18][19][20][21] A potential role for IL-6 in the thrombosis associated with human IBD is suggested by clinical evidence of elevated serum IL-6 concentration, with a corresponding increase in blood platelet count, in patients with active, but not inactive, IBD.…”