Background: Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by highly pruritic\neczematous lesions that are commonly treated with topical corticosteroids and calcineurin inhibitors. Side-effects\nand safety concerns associated with these agents restrict their use, and new, safe treatment options are therefore\nneeded. Recent reports suggest that serotonin, i.e. 5-hydroxytryptamine (5-HT) and the 5-HT2 receptor family may\ncontribute to inflammation and pruritus in the skin. The objective of this particular study was to investigate the\n5HT2B receptor antagonist AM1030 with respect to its anti-inflammatory profile and potential.\nMethods: AM1030 was tested in a set of distinct human and rodent in vitro and in vivo models, differing with\nrespect to e.g. T cell involvement, triggering stimulus, main read-outs and route of drug administration. The in vitro\nsystems used were staphylococcal enterotoxin A (SEA)-stimulated human peripheral blood mononuclear cells,\nlipopolysaccharide (LPS)-stimulated human primary monocytes, LPS-stimulated human THP-1 monocytes and\nLPS-stimulated mouse primary macrophages. The in vivo systems used were LPS- and SEA-induced cytokine\nproduction in the mouse, antigen-induced arthritis in the rat, glucose-6-phosphate isomerase-induced arthritis in\nthe mouse and delayed-type hypersensitivity reaction in the mouse. In addition, different cell populations were\nanalyzed with respect to their expression of the 5-HT2B receptor at the mRNA level.\nResults: AM1030 significantly reduced both T cell-dependent and T cell-independent inflammatory responses, in\nvivo and in vitro. Due to the low or absent expression of the 5-HT2B receptor on T cell populations, the influence of\nAM1030 in T cell-dependent systems is suggested to be mediated via an indirect effect involving\nantigen-presenting cell types, such as monocytes and macrophages.\nConclusion: Based on the wide range of model systems used in this study, differing e.g. with respect to species,\nT cell involvement, triggering stimuli, route of drug administration and read-outs, our results suggest a broad\nanti-inflammatory effect of AM1030 and identify the 5-HT2B receptor as a promising future target for\nanti-inflammatory intervention, e.g. in AD.
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