Expression Of Inflammatory Response Genes Research Articles

Induction of prostanoid, nitric oxide, and cytokine formation in rat bone marrow derived macrophages by activin A.

1. In this study we describe that activin A, a transforming growth factor (TGF) beta-like polypeptide affects the expression of inflammatory response genes and their products. 2. In rat bone marrow derived macrophages 15 nM activin A caused the stimulation of prostaglandin (PG) E2 and thromboxane (TX) A2 formation, production of nitrite as a marker for nitric oxide (NO) and the release of the cytokines tumour necrosis factor (TNF) alpha and interleukin (IL) -1beta. As shown by mRNA analysis induction of cyclo-oxygenase-2 and inducible nitric oxide synthase by activin A gave rise to the enhanced release of prostanoids and NO. 3. Costimulation of bone marrow derived macrophages with 15 nM activin A and 100 nM 12-O-tetradecanoyl-phorbol 13-acetate (TPA) potentiated the synthesis of prostanoids in a synergistic manner. With respect to NO formation the effect of activin A and TPA was additive. 4. In contrast to the nitrite production activin A induced PGE2 synthesis was susceptible to tyrosine kinase inhibition by genistein and tyrphostin 46 (IC50 was 10 and 20 microM, respectively). This observed inhibition was caused by the selective suppression of activin A induced cyclo-oxygenase-2 mRNA expression. Further, the release of TNFalpha in the presence of activin A was potentiated by tyrosine kinase inhibition. 5. In summary, we report that activin A exerts proinflammatory activity which results in the formation of prostanoids, NO and cytokines in rat bone marrow derived macrophages. Tyrosine kinase dependent and independent signalling pathways are involved leading to the increased synthesis of these metabolites. Based upon these results, we speculate that activin A may be considered as a possible component of inflammatory processes affecting at least the haematopoietic system.

Antioxidant-sensitive regulation of inflammatory-response genes in Kaposi's sarcoma cells.

Kaposi's sarcoma (KS) is a multifocal vascular lesion characterized by abnormal proliferation of endothelial-like KS cells linked to a pronounced leukocyte infiltration. KS lesions contain novel herpes-like DNA sequences, KSHV, hypothesized to originate from the viral pathogen for KS. Using cultured KS cells that retain the KSHV sequences, diverse signals, including tumor necrosis factor alpha, interleukin (IL) 1 beta, polyinosinic acid/polycytidylic acid and lipopolysaccharide, induced the expression of the cytokine IL-6 and cellular adhesion molecules involved in leukocyte recruitment, including vascular adhesion molecule 1 (VCAM-1) and intercellular adhesion molecule 1 (ICAM-1). The thiol-antioxidant pyrrolidine dithiocarbamate (PDTC) selectively inhibited > 90% of the activation of nuclear factor kappa B-like DNA binding activity in KS cells. PDTC also reduced by > 85% induced levels of VCAM-1 and IL-6 at the mRNA, protein, and functional levels in KS cells. In contrast, PDTC did not inhibit the induced expression of either ICAM-1 or E-selectin. These studies show that PDTC differentially modulates the expression of inflammatory response genes in KS cells that contain KSHV, suggesting that reduction-oxidation-sensitive events are involved in the regulation of these genes. These studies also suggest that thiol-antioxidants such as PDTC may play a potentially therapeutic role in the treatment of KS by preventing induction of specific inflammatory response genes that may be involved in the pathogenesis of KS.