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Glycosaminoglycans Inhibit Substance P‐ and IL‐33‐stimulated IL‐8 and TNF Release from Human‐Cultured Mast Cells
Author(s) -
Gross Amanda Rae,
Theoharides Theoharis C.
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.lb573
Subject(s) - degranulation , histamine , chemistry , heparin , glycosaminoglycan , cytokine , dermatan sulfate , chondroitin sulfate , mast cell , sulfation , tumor necrosis factor alpha , pharmacology , microbiology and biotechnology , biochemistry , medicine , endocrinology , immunology , receptor , biology
Glycosaminoglycans (GAGs) are long, linear, highly negatively charged carbohydrate chains that are known for their functional role in connective tissue, joint lubrication, and anticoagulant activity. Mast cells (MC) are hematopoietic tissue immune cells, involved in allergic and inflammatory reactions, which contain high amounts of GAGs, such as chondroitin sulfate (CS) and heparin, in their numerous secretory granules. In fact, heparin is synthesized and stored exclusively in MC granules and is thought to electrostatically store biogenic amines, such as histamine. A few previous studies reported that CS and heparin can inhibit the release of histamine from activated connective tissue rat and canine MC, respectively. However, the inhibitory potential of GAGs on human MC remains unknown. Here we report that CS had no effect on MC degranulation, as measured by beta‐hexosaminidase release, from LAD2 human‐cultured MC stimulated by the neuropeptide substance P (SP; 2 μM for 1 hr); however, pre‐incubation with CS did inhibit SP (1 μM for 24 hrs)‐induced IL‐8 and TNF release in a dose‐dependent manner. Specifically, CS 100 μg/mL inhibited IL‐8 and TNF release from SP‐stimulated LAD2 MC by 32% and 40%, respectively. Moreover, dermatan sulfate (DS) 5 μg/mL and heparin 40 μg/mL inhibited IL‐8 and TNF release from LAD2 MC stimulated by the cytokine IL‐33 (10 ng/mL for 24 hrs) by approximately 32% (p<0.05) and 39% (p<0.05), respectively. Similarly to heparin, at 37.5 μg/mL CS inhibited IL‐8 and TNF release from IL‐33‐stimulated LAD2 MC by approximately 36% and 43%, respectively. Preliminary, ongoing studies indicate that DS has an inhibitory effect on TNF gene expression at 6 hrs after IL‐33 stimulation. These results are important because IL‐33 is known to be an alarmin involved in allergic inflammation. GAGs from the tissue microenvironment or released by MC, themselves, upon activation, could inhibit the release of mediators from MC in a paracrine or autocrine fashion. It would be interesting to investigate the amount of these GAGs present in certain conditions involving allergic inflammation of the skin, such as atopic dermatitis, cutaneous mastocytosis, and psoriasis. DS may be formulated for local application, alone or in conjunction with other anti‐allergic molecules for the topical treatment of these diseases. Support or Funding Information Support for this project comes from the Tufts University Department of Integrative Physiology and Pathobiology (IPP) Fiscal Year 2016 Research Seed Funds.