Tumor necrosis factor-alpha inhibits expression of pulmonary surfactant protein.

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Abstract

Tumor necrosis factor-alpha (TNF-alpha) decreased the expression of pulmonary surfactant proteins SP-A and SP-B in human pulmonary adenocarcinoma cell lines. The effect of TNF alpha on SP-A content and mRNA in the pulmonary adenocarcinoma cell line, H441-4, was concentration and time dependent. TNF alpha decreased the cellular content of SP-A to less than 10% of control 48 h after addition. TNF alpha decreased de novo synthesis of SP-A and decreased the accumulation of SP-A in media. SP-A mRNA was decreased within 12 h of addition of TNF alpha, with nearly complete loss of SP-A mRNA observed after 24 h. Inhibitory effects of TNF alpha on SP-A mRNA were dose-related with nearly complete inhibition of SP-A mRNA caused by 25 ng/ml TNF alpha. The effects of TNF alpha on SP-A were distinct from the effects of interferon gamma which increased SP-A content approximately twofold in H441-4 cells. TNF alpha also decreased the content of SP-B mRNA. In contrast to the inhibitory effect of TNF alpha on SP-A and SP-B mRNA, TNF alpha increased mRNA encoding human manganese superoxide dismutase (Mn-SOD). TNF alpha did not inhibit growth, alter cell viability or beta-actin mRNA in either cell line. These in vitro studies demonstrate the marked pretranslational inhibitory effects of the cytokine, TNF alpha, on the expression of pulmonary surfactant proteins, SP-A and SP-B. The results support the concept that macrophage-derived cytokines may control surfactant protein expression.

Authors

J R Wispé, J C Clark, B B Warner, D Fajardo, W E Hull, R B Holtzman, J A Whitsett