Transforming growth factor-alpha (TGF-alpha) is a mitogenic peptide produced by tumor cells and by virally and chemically transformed cells in culture. TGF-alpha is almost certainly derived from its precursor protein (pro-TGF-alpha) by limited proteolysis, but the physiologically relevant processing enzyme(s) is(are) unknown. We now report that oncogenically transformed rat liver epithelial cells (known to secrete TGF-alpha) and Schwann cells in culture transfected with SV40 T-antigen (which are now reported to express mRNA encoding pro-TGF-alpha) contain membrane associated, neutral pH, serine proteinases which are elastase-like in their substrate specificity, but elastase is not known to be associated with these cell types. In both cell types, the enzyme is associated with a subcellular fraction enriched for microsomes and plasma membranes. Furthermore, the enzyme appears to be specifically induced 4-fold in the transformed epithelial cells as compared with the level of enzyme present in the nontransformed parental cells. The enzymes have been purified approximately 20,000-fold to near homogeneity (50-60 units/mg) and are virtually identical with regard to their molecular weights (38,000) and other physiochemical properties. Results obtained with numerous synthetic peptide substrates show the enzymes prefer nonpolar residues such as Ala and Val in the P1 and P2 positions, but promiscuity of cleavage specificity observed with long-chain peptide substrates is attributed to the absence of structure in these peptides. Thus, although these enzymes may be involved in processing pro-TGF-alpha at the plasma membrane of the cell, it is just as likely that these enzymes play other physiological roles in the parental and/or transformed cells and that there is no specific endoproteolytic processing enzyme of pro-TGF-alpha.
Pulmonary disease due to Mycobacterium avium complex (MAC) typically occurs in patients with impaired cellular immunity or chronic lung disease. Recently, there has been an increase in the number of reports of pulmonary disease caused by MAC occurring in otherwise healthy individuals, including those reporting recent hot tub use. It is not clear if this respiratory illness represents a true infectious process or a hypersensitivity pneumonitis. We report a case of diffuse pulmonary disease caused by MAC in an immunocompetent individual after hot tub use. The patient's clinical course, transbronchial lung biopsy results, and microbiologic examination findings all pointed to a hypersensitivity reaction due to MAC. With avoidance of the hot tub, and no pharmacological treatment, the patient had complete resolution within 2 months. In light of the number of new cases of "hot tub lung" in otherwise healthy individuals, clinicians should advise their patients of the potential risk associated with hot tub use.
While many liver tumors contain activated myc and ras oncogenes, the mechanisms by which these genes contribute to cellular transformation is poorly understood. Activated versions of the cellular oncogenes, c-myc and/or c-H-ras were transfected into normal rat liver epithelial cells to identify cellular pathways that are altered in the cells containing the oncogenes. The results of these and other investigations indicate that the biological properties associated with the transfection of c-myc include immortalization, reduced contact inhibition of growth, activation of phospholipase A2-mediated pathways, increased sensitivity to transformation with a ras gene, and greatly increased sensitivity to growth factors. The biological properties associated with the transfection of the ras gene include morphological transformation, anchorage-independent growth, tumorigenicity, increased phosphatidylinositol metabolism, the induction of growth-factor processing and secretion, which leads to (exogenous) growth factor-independent tumor growth, and a marked resistance to normal inhibitors of growth such as TGF-beta. It is proposed that the complementary actions of the myc and ras genes in cellular transformation may be related to the ras-induced secretion of autocrine growth factors by cells sensitized to their effects by the myc gene. The increased stimulus for growth coupled to a ras-induced insensitivity to growth inhibitors may lead to clonal expansion of these cells and tumor development.
In airway smooth muscle cells, interleukin (IL)-4 inhibited both carbachol-and caffeine-induced calcium mobilization from the sarcoplasmic reticulum (SR). Because of the known signaling pathways for IL-4 and importance of calcium uptake in maintaining SR calcium stores shared by agonists and caffeine, it was hypothesized that this rapid inhibitory effect might depend on phosphatidylinositol 3-kinase (PI3K) and on inhibition of calcium uptake by the SR. Enzyme-dispersed bovine trachealis cells were loaded with Fura-2/acetoxymethyl ester, and changes in cytosolic calcium were imaged in single cells. Cells were pretreated with inhibitors of PI3K, either wortmannin (100 nM), LY294002 [2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one] (50 M), or deguelin (100 nM). Calcium transients in response to carbachol (10 M) were significantly decreased to 0.34 Ϯ 0.10 of control after 20-min treatment with IL-4 but were 1.10 Ϯ 0.26 and 1.08 Ϯ 0.23 when wortmannin or deguelin, respectively, was added along with IL-4. LY294002 alone had nonspecific effects on transients. In other experiments, cyclopiazonic acid (CPA) (5 M), an inhibitor of SR calcium uptake, decreased carbachol-stimulated transients within 4 min to 0.83 Ϯ 0.08 of control (n ϭ 6). However, for cells treated with IL-4 (50 ng/ml) plus CPA, transients decreased significantly more, to only 0.51 Ϯ 0.05 (n ϭ 6; p Ͻ 0.05). Longer exposures to IL-4 and a higher concentration of CPA (30 M) gave similar results. It was concluded that IL-4 did not inhibit transients in the presence of PI3K antagonists but that it did in the presence of CPA. This suggested that IL-4 inhibited calcium transients by mechanisms dependent upon a wortmannin-sensitive PI3K but not by inhibition of calcium uptake into the SR.T helper-2 cytokines, including IL-4 and the closely related cytokine IL-13, have important and complex effects on airway inflammation and airway cells (Brusselle et al
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