Background: Many of the functions attributed to mast cells depend on the various pro-inflammatory mediators that are secreted upon mast cell activation. These include a panel of mast cell-specific proteases. In addition, recent studies have indicated that murine mast cells also express granzyme D, a protease previously thought to be confined to cytotoxic lymphocytes. Here, we address the human relevance of the latter findings by investigating whether human mast cells express granzyme H, the granzyme that may represent the functional counterpart to murine granzyme D. Methods: Cord blood-derived mast cells, LAD2 cells and skin mast cells in situ were evaluated for their expression of granzymes using quantitative PCR, Western blot analysis and immunostaining. Mast cells were activated by either calcium ionophore stimulation or IgE receptor cross-linking. Results: Cord blood-derived mast cells and LAD2 cells were shown to express granzyme H and B mRNA, while granzyme A, K and M expression was undetectable. Mast cell activation by either calcium ionophore or IgE receptor cross-linking caused down-regulated expression of granzyme H. In contrast, granzyme B expression was up-regulated by the same stimuli. Granzyme H expression was also confirmed at the protein level, as shown by both Western blot analysis and confocal microscopy. Further, we show that granzyme H is expressed by human skin mast cells in situ. Conclusions: The present findings implicate granzyme H as a novel protease expressed by human mast cells and support earlier findings obtained in natural killer cells suggesting that granzymes B and H are reciprocally regulated.
Mast cells are fascinating, multifunctional, tissue-dwelling cells that have been traditionally associated with the allergic response. However, recent studies suggest these cells may be capable of regulating inflammation, host defense, and innate immunity. The purpose of this review is to present salient aspects of mast cell biology in the context of mast cell function in physiology and disease. After their development from bone marrow-derived progenitor cells that are primed with stem cell factor, mast cells continue their maturation and differentiation in peripheral tissue, developing into two well-described subsets of cells, MC(T) and MC(TC) cells. These cells can be distinguished on the basis of their tissue location, dependence on T lymphocytes, and their granule contents. Mast cells can undergo activation by antigens/allergens, superoxides, complement proteins, neuropeptides, and lipoproteins. After activation, mast cells express histamine, leukotrienes, and prostanoids, as well as proteases, and many cytokines and chemokines. These mediators may be pivotal to the genesis of an inflammatory response. By virtue of their location and mediator expression, mast cells may play an active role in many diseases, such as allergy, parasitic diseases, atherosclerosis, malignancy, asthma, pulmonary fibrosis, and arthritis. Recent data also suggest that mast cells play a vital role in host defense against pathogens by elaboration of tumor necrosis factor alpha. Mast cells also express the Toll-like receptor, which may further accentuate their role in the immune-inflammatory response. This chapter summarizes the many well-known and novel functional aspects of human mast cell biology and emphasizes their unique role in the inflammatory response.
Gueck T, Aschenbach JR, Fuhrmann H.
Institute of Physiological Chemistry, Faculty of Veterinary Medicine, University of Leipzig, An den Tierkliniken 1, 04103 Leipzig, Germany. gueck@-
We investigated the influence of vitamin E on mediator activity and release in a canine mastocytoma cell line (C2) as a model for canine atopic dermatitis. Cells were incubated without and with vitamin E (100 microm) for 24 h. The histamine and prostaglandin D2 (PGD2) release as well as the chymase and tryptase activity were measured. To stimulate the PGD2 and histamine release, cells were incubated with the wasp venom peptide mastoparan (50 microm) for 30 or 45 min. Nonstimulated as well as mastoparan-stimulated histamine and PGD2 release was reduced significantly in vitamin E-treated cells. The activity of chymase tended to decrease, but the tryptase activity of C2 cells was not influenced by vitamin E. These results indicate that vitamin E decreased the production and release of inflammatory mediators in C2 cells, suggesting that vitamin E might have a possible beneficial effect in inflammatory diseases.