Adrenergic receptors are expressed on the surface of inflammation-mediating cells, but their potential role in the regulation of the inflammatory response is still poorly understood. The objectives of this work were to study the effects of α2-adrenergic agonists on the inflammatory response in vivo and to determine their mechanism of action. In two mouse models of inflammation, zymosan air pouch and thioglycolate-induced peritonitis models, the i.m. treatment with xylazine or UK14304, two α2-adrenergic agonists, reduced neutrophil migration by 60%. The α2-adrenergic antagonist RX821002 abrogated this effect. In flow cytometry experiments, the basal surface expression of L-selectin and CD11b was modified neither in murine nor in human neutrophils upon α2-agonist treatment. Similar experiments in HUVEC showed that UK14304 prevented the activation-dependent upregulation of ICAM-1. In contrast, UK14304 augmented electrical resistance and reduced macromolecular transport through a confluent HUVEC monolayer. In flow chamber experiments, under postcapillary venule-like flow conditions, the pretreatment of HUVECs, but not neutrophils, with α2-agonists decreased transendothelial migration, without affecting neutrophil rolling. Interestingly, α2-agonists prevented the TNF-α–mediated decrease in expression of the adherens junctional molecules, VE-cadherin, β-catenin, and plakoglobin, and reduced the ICAM-1–mediated phosphorylation of VE-cadherin by immunofluorescence and confocal analysis and Western blot analysis, respectively. These findings indicate that α2-adrenoceptors trigger signals that protect the integrity of endothelial adherens junctions during the inflammatory response, thus pointing at the vascular endothelium as a therapeutic target for the management of inflammatory processes in humans.

Diphenylamine-based nonsteroidal antiinflammatory drugs (NSAIDs) are able to cause in vitro the shedding of L-selectin. The aim of this work was to determine the physiologic relevance of L-selectin shedding in the antiinflammatory effect exerted by NSAIDs in vivo. Chemical compounds structurally related to NSAIDs -including diphenylamine, N-phenylanthranilic acid (N-Ph), diphenylacetic acid -as well as the traditional NSAID indomethacin were studied using the zymosan air-pouch mouse model. Animals intramuscularly pretreated with indomethacin or N-Ph, but not with diphenylamine or diphenylacetic acid, showed a significant dose-dependent reduction in the number of neutrophils compared with untreated animals (N-Ph, IC50 = 6.7 mg/kg). Except for indomethacin, none of these compounds caused any significant reduction in cyclooxygenase-1 activity in vivo. In flow chamber experiments, N-Ph reduced the capability of human neutrophils to pass across the endothelial barrier by interfering with leukocyte rolling step on HUVEC. N-Ph, but not diphenylacetic acid, induced activationindependent L-selectin shedding in mouse neutrophils. Interestingly, N-Ph exerted an antiinflammatory effect similar to that of the anti-L-selectin blocking antibody Mel-14, although no additive action was observed when both compounds were combined. These data suggest that the L-selectin shedding induced by NSAIDs may be involved in the antiinflammatory action exerted by these compounds in clinical settings. Keywords:Air-pouch mouse model r L-selectin r Nonsteroidal antiinflammatory drugs r N-phenylanthranilic acid See accompanying Commentary by Zarbock and RossaintCorrespondence: Prof. Federico Díaz-González e-mail: federico.diaz.gonzalez@gmail.com IntroductionThe recruitment of leukocytes into tissues during the inflammatory response is preceded by a highly coordinated sequence of adhesive events between flowing leukocytes and endothelial cells, a process known as the adhesion cascade. Members of three major C 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu 56Ada Herrera-García et al. Eur. J. Immunol. 2013. 43: 55-64 adhesion receptor families have been implicated in this cascade: selectins, integrins, and the immunoglobulin superfamily [1,2]. In the field of inflammation, much effort is currently focused on developing antagonists of adhesion receptors, an approach known as antiadhesive therapy. This strategy is based on the assumption that if any one of the sequential steps of the adhesion cascade is inhibited, the inflammatory response is consequently suppressed or, at least, ameliorated [3,4]. Although antiadhesive therapies targeting the major leukocyte integrins LFA-1, Mac-1, and VLA-4 have proven to be relatively successful in several human inflammatory disorders [4], the inhibition of selectins and their ligands has only proven beneficial in certain animal models of inflammation [5][6][7][8], with apparently only limited clinical effects on human inflammatory conditions [9]. Nonsteroidal antiinflammatory drugs (NSAIDs...

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Synovial B cells from patients with RA and patients with PsA express different antigen-presenting cell phenotypes, suggesting that this cell type plays a dissimilar role in the pathogenesis of each disease.

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