Background Peripheral blood mononuclear cells (PBMCs) are thought to play a key role in the pathogenesis and progress of systemic scleroderma (SSc) with patients displaying distinct shifts in count, receptor expression profile and cytokine secretion patterns. SSc-IgG with elevated anti-AT1R (angiotensin II type 1 receptor)/ETAR (endothelin-1 type A receptor) -AAb (autoantibody) titers have been correlated to disease severity and progression1. It remains poorly understood through which pathways SSc- IgG mediates its effects.
Objectives In this study we sought to analyze the expression patterns of THP-1 cells (a monocytic cell line) after SSc-IgG application and their reversibility through application of numerous pharmacological inhibitors.
Methods Transcription of IL-8- and CCL-18 in THP-1-cells after SSc-IgG and normal IgG stimulation was quantified by qPCR. Stimulations of THP-1 cells with total IgG of phenotypically different groups of SSc patients as well as ET-1 and AT-2 were carried out. In addition, stimulation with pharmacological inhibitors was conducted in a dose-dependent-manner. The results were quantified by IL-8- and CCL18-ELISA of the supernatants.
Results Expression of IL-8 and CCL-18 is induced by SSc-IgG treatment in comparison to normal IgG which does not follow this trend. IL-8 secretion of THP-1 cells upon SSc-IgG stimulation is mediated through specific autoantibody effects and transduced through NF-κB, ERK-, and AP-1 pathways. CCL-18 secretion of THP-1 cells upon SSc-IgG stimulation is not mediated through aforementioned pathways.
Conclusions A stable cell culture system able to reproduce previous PBMC data on IL-8 and CCL-18 induction upon SSc-IgG-treatment could be established and insight was gained regarding key pathways which are involved in the transduction leading to IL-8 secretion. The effects of specific surface receptor expression profiles on transduction remain to be elucidated.
Günther, J., Rademacher, J., van Laar, J.M. et al. Semin Immunopathol (2015) 37: 529.
Disclosure of Interest None declared
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