Characterization and modulation of canine mast cell derived eicosanoids

Abstract

Mast cells play an important role in both innate and acquired immunity as well as several pathological conditions including allergy, arthritis and neoplasia. They influence these processes by producing a variety of mediators including cytokines, chemokines and eicosanoids. Very little is currently known about the spectrum of inflammatory mediators, particularly eicosanoids (prostaglandins and leukotrienes), produced by canine mast cells. This is important since modulating mast cell derived eicosanoids may help in the treatment of autoimmune and inflammatory disorders. The purpose of this study was to investigate the spectrum of eicosanoids produced by normal canine mast cells and to evaluate the effects of cytokines and non-steroidal anti-inflammatory mediators (NSAIDS) on eicosanoid production and release. Canine bone marrow derived cultured mast cells (cBMCMCs) expressed COX-1, COX-2, and 5-LOX and synthesized and released PGD2, PGE2, LTB4, and LTC4 following activation by a variety of stimuli. The selective COX-2 NSAIDs carprofen (Rimadyl®) and deracoxib (Deramaxx®) inhibited PGD2 and PGE2 production but only slightly inhibited LTB4 and LTC4. The mixed COX-1/COX-2 inhibitor piroxicam blocked PGD2 and PGE2 production, but upregulated LTC4 following treatment while tepoxilan (Zubrin®), a pan COX/LOX inhibitor, markedly reduced the production of all eicosanoids. The LOX inhibitor nordihydroguaiaretic acid (NDGA) prevented LTB4/LTC4 release and BMBMC degranulation. Pre-incubation of cBMCMCs with IL-4 and SCF sensitized these cells to degranulation in response to substance P. In conclusion, canine BMCMCs produce an array of eicosanoids similar to those produced by mast cells from other species. Tepoxilan appeared to be the most effective NSAID for blocking eicosanoid production and thus may be useful for modulating mast cell mediated responses in dogs.

Review: Innate immunity, lipid metabolism and nutrition in canine atopic dermatitis

“…Canine mast cells and mast cell lines have been shown to release histamine, TNFα, eicosanoids [prostaglandin (PG) D 2 , PGE 2 and leukotriene (LT) B4 and C4], neutral proteases (chymase and tryptase), other proteases (e.g. matrix metalloproteinase 9), IL‐3, IL‐4, IL‐6, IL‐13, granulocyte–macrophage colony‐stimulating factor (GM‐CSF), CCL5 (regulated upon activation normal T‐cell expressed and secreted; RANTES), CCL2 (monocyte chemotactic protein 1) and CCL3 (macrophage inhibitory protein 1α) …”

“…In one study, mast cells harvested from normal dogs, dogs with AD and dogs sensitized to Ascaris suum showed no apparent differences in spontaneous or IgE‐mediated histamine releasibility . Furthermore, intradermal injection of substance P (which may induce mast cell degranulation) induced smaller wheals in the skin of atopic dogs relative to those in normal dogs . However, substance P has also been demonstrated to induce vasodilatation directly via its actions on endothelial neurokinin receptor‐1 in humans and in dogs .…”

“…It has been demonstrated to mediate pruritus in mouse models via binding to neurokinin 1 receptors . Substance P has also been demonstrated to induce degranulation of mast cells in the dog, which may contribute to pruritus via the release of inflammatory mediators . Topical use of vanilloid compounds, such as capsaicin, may decrease pruritus through local depletion of substance P .…”

CD25 Is Expressed by Canine Cutaneous Mast Cell Tumors but not by Cutaneous Connective Tissue Mast Cells

“…In the context of immunomodulation, it is also noteworthy that CD25 expression can be induced on dendritic cells by a combination of tumor necrosis factor-a and prostaglandin E2 (PGE2), the latter of which is synthesized by mast cells. 26,38 It could be speculated that PGE2 production by mast cells contributes to their CD25 expression level.…”

Involvement of Leukotriene B4 Released from Keratinocytes in Itch-associated Response to Intradermal Interleukin-31 in Mice

“…5-Lipoxygenase is a key enzyme involved in the production of LTB 4 (42). In the skin, 5-lipoxygenase is www.medicaljournals.se/acta expressed mainly in the keratinocytes (43) and mast cells (44). IL-31 receptors are expressed in the keratinocytes, but not in the mast cells (4, 6, 45; Fig.…”