A 1.6-kilobase pair cDNA was isolated from a human T-cell-derived expression library that encodes a novel eosinophil chemoattractant (designated ecalectin) expressed during allergic and parasitic responses. Based on its deduced amino acid sequence, ecalectin is a 36-kDa protein consisting of 323 amino acids. Although ecalectin lacks a hydrophobic signal peptide, it is secreted from mammalian cells. Ecalectin is not related to any known cytokine or chemokine but rather is a variant of human galectin-9, a member of the large family of animal lectins that have affinity for -galactosides. Recombinant ecalectin, expressed in COS cells and insect cells, exhibited potent eosinophil chemoattractant activity and attracted eosinophils in vitro and in vivo in a dose-dependent manner but not neutrophils, lymphocytes, or monocytes. The finding that the ecalectin transcript is present in abundance in various lymphatic tissues and that its expression increases substantially in antigen-activated peripheral blood mononuclear cells suggests that ecalectin is an important T-cell-derived regulator of eosinophil recruitment in tissues during inflammatory reactions. We believe that this is the first report of the expression of an immunoregulatory galectin expressed by a T-cell line that is selective for eosinophils.
Abstract. Whether or not a nontransformed, mature mouse mast cell (MC) or its committed progenitor can change its granule protease phenotype during inflammatory responses, has not been determined. To address this issue, the granule morphology and protease content of the MC in the jejunum of BALB/c mice exposed to Trichinella spiralis were assessed during the course of the infection. Within 1 wk after helminth infection of the mice, increased numbers of MC appeared in the crypts at the base of the villi, and by wk 2 the number of MC throughout the villi increased by ~25-fold. Shortly after the peak of the mastocytosis, the intraepithelial population of MC disappeared, followed by a progressive loss of lamina propria MC. The presence of stellate-shaped granules containing crystalline structures in intraepithelial MC at the height of infection and the retention of such granules with fragmented crystals in lamina propria MC during resolution of the mastocytosis suggest that MC migrate during the various phases of the inflammation. As assessed by immunohistochemical analyses of serial sections, predominant chymase phenotypes were observed at the height of the infection in the muscle that expressed mouse MC protease (mMCP) 5 without mMCP-1 or mMCP-2 and in the epithelium that expressed mMCP-1 and mMCP-2 without mMCP-5. Accompanying these two MC populations were transitional forms in the submucosa that expressed mMCP-2 and mMCP-5 without mMCP-1 and in the lamina propria that expressed rnMCP-2 alone. These data suggest that jejunal MC sequentially express mMCP-2, cease expressing mMCP-5, and finally express mMCP-1 as the cells progressively appear in the submucosa, lamina propria, and epithelium, respectively. In the recovery phase of the disease, MC sequentially cease expressing mMCP-1, express mMCP-5, and finally cease expressing mMCP-2 as they present at the tips of the villi, the base of the villi, and the submucosa, respectively. That MC can reversibly alter their protease phenotypes suggests that a static nomenclature with fixed functional implications is inadequate to describe MC populations during an inflammatory process within a particular tissue.
Effects of transforming growth factor beta (TGF-beta) on IgA production by LPS-stimulated B cells have been studied. TGF-beta itself could augment polyclonal IgA production in concomitant inhibition of polyclonal IgM and IgG1 production. Furthermore, TGF-beta and IL-5 additively augmented IgA production. TGF-beta exerted its activity early in the culture (by 2 d in a 5-d culture) and IL-5 was required late in the culture. Surface IgA- (sIgA-) B cells responded to TGF-beta for the development of IgA-secreting cells. By contrast, sIgA+ B cells, but not sIgA- B cells, responded to IL-5 for IgA production. These results suggest that TGF-beta has a differential role in the induction of IgA production from IL-5 on murine-activated B cells.
SummaryInterleukin 5 (1175) has been suggested to be involved in the growth and differentiation of B cells and eosinophils. Especially, Ly-1+ B cells, which have been considered to produce autoantibodies, are selectively developed by this lymphokine in long-term bone marrow culture . To envisage the possible engagement of IL5 in the development of these cells in vivo, transgenic mice carrying the mouse IL5 gene ligated with a metallothionein promoter were generated . Transgenic mice carrying the 1175 gene exhibited elevated levels of 11,5 in the serum and an increase in the levels of serum IgM and IgA. A massive eosinophilia in peripheral blood, bone marrow, and spleen, and an infiltration ofmuscle and liver with eosinophils, were observed. When cadmiumcontaining saline was injected intraperitoneally into transgenic mice, IM production was augmented about five times within 24 h, and a distinctive Ly-1 + B cell population became apparent in the spleen after 5 d. 1175 receptors were detected on those cells by monoclonal antibodies against IL-5 receptors. Another interesting finding in these transgenic mice was an increase in polyreactive anti-DNA antibodies of IgM class. It is suggested, therefore, that aberrant expression of the IL5 gene may induce accumulation of Ly-1+ B cells and eosinophils. Furthermore, this IL5 transgenic mouse can be a model mouse for eosinophilia, and we can determine the role of IL5 in the differentiation of Ly-1 + B cells and eosinophils by using this mouse.
We have examined the cytokine regulation of IgE-dependent prostaglandin (PG) D2 generation in mouse mast cells by assessing the changes in the levels of the transcript, translated protein, and activity of the enzymes involved in the synthesis of PGD2 from endogenous arachidonic acid. When mouse mast cells, derived by culture of bone marrow cells with WEHI-3 cell-conditioned medium as a source of interleukin (IL)-3 (BMMC), were cultured in recombinant ckit ligand (KL), sensitized with IgE, and stimulated with antigen, PGD2 generation increased 3-fold; when KL was combined with IL-3, IL-9, or IL-10, PGD2 generation increased 6-8-fold above that produced by the cells cultured in IL-3 alone. The increased IgE-dependent PGD2 generation by BMMC was apparent after 1 day of culture, reached a maximum after 2-4 days of culture, and was dose-dependent for KL and for each of the accessory cytokines. IgE-dependent generation of leukotriene C4 increased 2-fold after the cells were cultured with KL and was not increased by the addition of IL-3, IL-9, or IL-10. Assays for steady-state transcripts by RNA blotting, for protein by SDS-PAGE/immunoblotting, and for function by enzymatic activities revealed that KL alone stimulated the increased expression of cytosolic phospholipase A2 (cPLA2), prostaglandin endoperoxide synthase (PGHS)-1, and the terminal enzyme, hematopoietic PGD2 synthase, without a change in expression of 5-lipoxygenase. IL-3, IL-9, and IL-10 each enhanced the KL-induced expression of PGHS-1. In contrast, transcripts for PGHS-2, which were detected transiently after the cells had been cultured for 5 h in KL+IL-3, were not expressed during the period of subsequent increase in IgE-dependent PGD2 generation. These findings demonstrate that KL up-regulates expression of cPLA2, PGHS-1, and hematopoietic PGD2 synthase, leading to a relatively selective increase in IgE-dependent production of PGD2 from endogenously released arachidonic acid in BMMC, and they provide the first example of cytokine regulation of hematopoietic PGD2 synthase.
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