BackgroundB cells exert their pathogenic action in rheumatoid arthritis (RA) locally in the synovium. This study was undertaken to elucidate the chemokines responsible for the recruitment of B cells in the inflamed synovium, taking into account that the rich chemokine milieu present in the synovial tissue can fine-tune modulate discrete chemokine receptors.MethodsExpression levels of chemokine receptors from the CC and CXC family, as well as CD27, were assessed by flow cytometry in CD20+ mononuclear cells isolated from the peripheral blood (PB) and synovial fluid (SF) of RA and psoriatic arthritis patients. Transwell experiments were used to study migration of B cells in response to a chemokine or in the presence of multiple chemokines.ResultsB cells from the SF of arthritis patients showed a significant increase in the surface expression of CCR1, CCR2, CCR4, CCR5 and CXCR4 with respect to PB. Conversely, SF B cells expressed consistently lower amounts of CXCR5, CXCR7 and CCR6, independent of CD27 expression. Analysis of permeabilized B cells suggested internalization of CXCR5 and CCR6 in SF B cells. In Transwell experiments, CCL20 and CXCL13, ligands of CCR6 and CXCR5, respectively, caused a significantly higher migration of B cells from PB than of those from SF of RA patients. Together, these two chemokines synergistically increased B-cell migration from PB, but not from SF.ConclusionsThese results suggest that CXCL13 and CCL20 might play major roles in RA pathogenesis by acting singly on their selective receptors and synergistically in the accumulation of B cells within the inflamed synovium.Electronic supplementary materialThe online version of this article (10.1186/s13075-018-1611-2) contains supplementary material, which is available to authorized users.
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...
Primary Sjögren’s syndrome (pSS) is an autoimmune exocrinopathy in which the role that the immune response plays in reducing exocrine gland function, including the glandular microenvironment of cytokines, has not been fully understood. Epithelial cells from biopsies of human parotid gland (HPG) were used to establish a model of human salivary gland in vitro. In this model, the functional consequences of several proinflammatory soluble factors present in the pSS glandular microenvironment were assessed. Stimulation with isoproterenol and calcium produced a significant increase in the basal activity of amylase in the HPG cell supernatants. Under these conditions, the presence of TNF-α and CXCL12 increased amylase mRNA cellular abundance, but reduced the amylase activity in the cell-free supernatant in a dose-dependent manner. IL-1β and IFN-γ, but not TGF-β, also diminished amylase secretion by HPG cells. These results suggest that the glandular microenvironment of cytokine, by acting post-transcriptionally, may be responsible, at least in part, for the reduced exocrine function observed in pSS patients. These data may help to a better understanding of the pathogenesis of SS, which in turn would facilitate the identification of new therapeutic targets for this disorder.
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