Inhibitory Action of Tetradrine on Macrophage Production of Interleukin-1 (IL-1)-Like Activity and Thymocyte Proliferation

"Tetrandrine is a bisbenzylisoquinoline alkaloid which has been shown to exhibit antifibrotic activity against silicosis. Tetrandrine is characterized by its strong binding to alveolar macrophages and inhibition of particle-induced respiratory burst activity in these phagocytes. In contrast, tubocurine and tubocurarine are structurally similar to tetrandrine but exhibit little effect on fibrosis or activation of alveolar macrophages. The objective of the present study was to test the effect of tetrandrine on macrophage production of monokines in response to occupational dusts, and to determine tetrandrine's effect on monokine-medicated cell growth using a mouse thymocyte proliferation assay and lipopolysaccharide (LPS) as a positive control. Stimulation of alveolar macrophages by respirable silica dust resulted in a release of monokines which caused a fourfold increase in thymocyte proliferation. Coal dust, on the other hand, had no effect on macrophage production of this cytokine. Tetrandrine was found to exhibit a dose-dependent inhibition of monokine release from both silica and LPS-stimulated alveolar macrophages. In experiments where thymocytes were directly treated with tetrandrine, a dose-dependent inhibition of thymocyte proliferation was noted with both interleukin-1- (IL-1) specific and nonspecific mitogenic (concanavalin A) actions. In contrast to the inhibitory potency of tetrandrine, tubocurarine was found to have no effect on either the production of monokines by LPS-stimulated alveolar macrophages or IL-I-mediated thymocyte proliferation. These results provide a correlation between the ant:fibrotic effect of tetrandrine and inhibition of macrophage activation. INTRODUCTIONThe pathogenesis of chronic pulmonary fibrosis caused by inhalation of occupational dusts has been associated with abnormal activation of alveolar macrophages such as the release of various cytokines capable of inducing fibroblast proliferation and collagen synthesis. These macrophage-derived cytokines include interleukin-1 (IL-1), tumor necrosis factor (TNF), platelet-derived growth factor (PDGF), transforming growth factor-B (TGF-(B), macrophage derived growth factor (MDGF), and interferon [1, 2].Interleukin-1 is a major macrophage-derived cytokine that has been shown to exhibit multiple biological effects on a variety of target cells. It is known to cause leukocyte [3, 4] and endothelial cell activation [5, 6], and to affect the synthesis and maintenance of the extracellular matrix by stimulation of fibroblast proliferation [7-9], synthesis of collagens [10] and gluco-saminoglycans [11], and prostaglandin E2 production [12]. In addition, IL-1 plays an important role in the initiation of an immune response through its direct activation of lymphocytes and stimulation of the production of other cytokines, such as interferons and hemopoietic colony-stimulating factors, needed for the expression of an immune response [13]. As a major cytokine in the immune-inflammatory sequela, IL-1 is also produced by epidermal, epithelial, lymphoid, and vascular tissues after infection, injury, or antigenic challenge [14]. Agents such as lipopolysaccharide (LPS), phorbol myristate acetate (PMA), immune complexes, and particulates are known to activate the synthesis and release of IL-1 by monocytes and macrophages [15]. These substances also trigger intracellular signals leading to altered arachidonic acid metabolism. Although the mechanism is still not clear, prostaglandins have been shown to suppress IL-1 translation via the induction of cyclic adenosine-monophosphate (CAMP), whereas leukotrienes produce a positive signal for IL-1 production [13]."