Chondroitin sulfate inhibits secretion of TNF and CXCL8 from human mast cells stimulated by IL-33.

Abstract

Glycosaminoglycans (GAGs) are linear, highly negatively charged carbohydrate chains present in connective tissues. Chondroitin sulfate (CS) and heparin (Hep) are also found in the numerous secretory granules of mast cells (MC), tissue immune cells involved in allergic and inflammatory reactions. CS and Hep may inhibit secretion of histamine from rat connective tissue MC, but their effect on human MC remains unknown. Human LAD2 MC were pre-incubated with CS, Hep, or dermatan sulfate (DS) before being stimulated by either the peptide substance P (SP, 2 μM) or the cytokine IL-33 (10 ng/mL). Preincubation with CS had no effect on MC degranulation stimulated by SP, but inhibited TNF (60%) and CXCL8 (45%) secretion from LAD2 cells stimulated by IL-33. Fluorescein-conjugated CS (CS-F) was internalized by LAD2 cells only at 37 °C, but not 4 °C, indicating it occurred by endocytosis. DS and Hep inhibited IL-33-stimulated secretion of TNF and CXCL8 to a similar extent as CS. None of the GAGs tested inhibited IL-33-stimulated gene expression of either TNF or CXCL8. There was no effect of CS on ionomycin-stimulated calcium influx. There was also no effect of CS on surface expression of the IL-33 receptor, ST2. Neutralization of the hyaluronan receptor CD44 did not affect the internalization of CS-F. The findings in this article show that CS inhibits secretion of TNF and CXCL8 from human cultured MC stimulated by IL-33. CS could be formulated for systemic or topical treatment of allergic or inflammatory diseases, such as atopic dermatitis, cutaneous mastocytosis, and psoriasis. © 2018 BioFactors, 45(1):49-61, 2019.