Dexamethasone inhibition of leucocyte adhesion to rat mesenteric postcapillary venules: role of intercellular adhesion molecule 1 and KC

Abstract

Background-A previous study showed that the glucocorticoid dexamethasone, at doses of 100 µg/kg and above, inhibited leucocyte adhesion to rat mesenteric postcapillary venules activated with interleukin 1 (IL-1 ), as assessed by videomicroscopy. Aims-To identify whether the adhesion molecule, intercellular adhesion molecule 1 (ICAM-1), or the chemokine KC could be targeted by the steroid to mediate its antiadhesive eVect. Methods-Rat mesenteries were treated with IL-1 (20 ng intraperitoneally) and the extent of leucocyte adhesion measured at two and four hours using intravital microscopy. Rats were treated with dexamethasone, and passively immunised against ICAM-1 or KC. Endogenous expression of these two mediators was validated by immunohistochemistry, ELISA, and the injection of specific radiolabelled antibodies. Results-Dexamethasone greatly reduced IL-1 induced leucocyte adhesion, endothelial expression of ICAM-1 in the postcapillary venule, and release of the mast cell derived chemokine KC. Injection of specific antibodies to the latter mediators was also extremely eVective in downregulating (>80%) IL-1 induced leucocyte adhesion. Conclusions-Induction by IL-1 of endogenous ICAM-1 and KC contributes to leucocyte adhesion to inflamed mesenteric vessels. Without excluding other possible mediators, these data clearly show that dexamethasone interferes with ICAM-1 expression and KC release from mast cells, resulting in suppression of leucocyte accumulation in the bowel wall, which is a prominent feature of several gastrointestinal pathologies. (Gut 1999;45:705-712)

Mechanisms by which endogenous glucocorticoid protects against indomethacin-induced gastric injury in rats

“…It is assumed that the effect of corticosterone on the microvascular permeability is brought about by its inhibitory action on gastric hypermotility induced by indomethacin through amelioration of glucose metabolism. On the other hand, it is possible that corticosterone directly inhibits the microcirculatory disturbances by strengthening the vascular integrity (32). Indeed, the present study showed that a deficiency of glucocorticoids by itself induced a significant increase in gastric microvascular permeability in adrenalectomized rats and that this increase was totally prevented by corticosterone replacement.…”

Mechanisms underlying the anti-inflammatory actions of boswellic acid derivatives in experimental colitis

“…Although the two agents appear equally effective in this model, it is not clear to what extent they share similar modes of action at the cellular and/or molecular level. Cortisol is known to exert immunomodulatory effects that have not yet been attributed to AKBA, including effects on lymphocyte differentiation, cytokine synthesis, and chemokine release from mast cells (30,37). However, dexamethasone and AKBA do appear to share some common targets, including downregulation of 5-lipoxygenase (5-LO) and inhibition of endothelial CAM expression (26,33,37).…”

“…Cortisol is known to exert immunomodulatory effects that have not yet been attributed to AKBA, including effects on lymphocyte differentiation, cytokine synthesis, and chemokine release from mast cells (30,37). However, dexamethasone and AKBA do appear to share some common targets, including downregulation of 5-lipoxygenase (5-LO) and inhibition of endothelial CAM expression (26,33,37). Since it has been shown that 5-LO inhibition abrogates the P-selectin upregulation elicited by intestinal ischemia-reperfusion, it is possible that either or both agents downregulate the expression of this adhesion molecule, at least in part, via 5-LO (10).…”

A Novel Biological Activity for Galectin-1

“…It is well known that IL-1␤ induces the synthesis and/or release of chemokines and nonprotein chemoattractants, these together with endothelial adhesion molecule up-regulation, promote PMN extravasation. [33][34][35][36] As the Gal-1 anti-migratory effect did not seem to be linked to an inhibition of IL-1␤ induced mediator generation, we tested the hypothesis that Gal-1 could affect a specific step in the PMN interaction with the activated endothelium. We chose the mouse mesentery for intravital microscopy to test this hypothesis because it has been shown that in this model IL-1␤ attracts predominantly blood-borne PMNs.…”