RESUMO
Helminthic infections, which are particularly common in the developing world, are associated with the accumulation of mucosal mast cells (MMCs) in the epithelial layer of the gut. Although intestinal parasite infection models argue that IL-18 plays a role in MMC differentiation and function, the direct effect of IL-18 on MMCs is still not well understood. To clarify the role of IL-18 in mast cell biology, we analyzed gene expression changes in MMCs in vitro. DNA microarray technology uncovered a group of chemokines regulated by IL-18, among which Ccl1 (I-309, TCA-3) showed the highest up-regulation. Ccl1 induction was only transient in mast cells and was characteristic for both immature and mature MMCs, but not for connective tissue-type mast cells. IL-18 exerts its Ccl1-inducing effect in MMCs primarily via the activation of NFkappaB. Moreover, IL-18 was effective both in the absence and the presence of IgE-antigen complex. The Ccl1 receptor (CCR8) is known to be expressed by T(h)2 cells and is involved in their recruitment. Our present findings suggest that IL-18 may contribute to mast cell-influenced Th2 responses by inducing Ccl1 production.
Assuntos
Quimiocina CCL1/metabolismo , Interleucina-18/metabolismo , Mastócitos/metabolismo , Células Th1/metabolismo , Células Th2/metabolismo , Animais , Quimiocina CCL1/antagonistas & inibidores , Quimiocina CCL1/genética , Dinitrofenóis/metabolismo , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Imunidade nas Mucosas , Interleucina-18/genética , Interleucina-18/imunologia , Interleucina-18/farmacologia , Mastócitos/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Análise em Microsséries , NF-kappa B/metabolismo , Óxido Nítrico/metabolismo , Albumina Sérica/metabolismo , Transdução de SinaisRESUMO
Mast cells are rich sources of proteases, such as tryptases and chymases that control many physiological and pathological processes, for example vascular permeability, smooth muscle cell proliferation or extracellular matrix remodeling. Murine mucosal mast cells mature under the influence of TGF-beta and play a role in asthmatic and anti-helminthic immune responses. In an attempt to identify novel genes that are highly upregulated during mucosal mast cell differentiation, we detected HtrA1 protease as a novel protein in mast cells by microarray experiments. HtrA1 level was much higher in murine mucosal than in connective tissue-type mast cells. Furthermore, HtrA1 is not localized in the secretory granules and is constitutively secreted by human mast cells. Although HtrA1 has been attributed a TGF-beta-inhibitory activity, it did not show any influence on TGF-beta-induced mucosal mast cell differentiation. As many extracellular target proteins have been suggested for HtrA1, this protease may participate in the mast cell-induced extracellular remodeling.
