Tumor necrosis factor-alpha-induced lung cell expression of antiapoptotic genes TRAF1 and cIAP2

Tumor necrosis factor (TNF) receptor (TNFR)-associated factors 1 and 2 (TRA F1 and TRAF2) and inhibitor of apoptosis proteins cIAP1 (MIHB) and cIAP2 (M IHC) were recently identified as proteins that associate with the TNF-alpha receptors TNFRI (p55) and TNFRII (p75) and inhibit TNF-alpha-induced progr ammed cell death or apoptosis, In the original reports. TRAF1 expression, u nlike the ubiquitous TRAF2, was restricted to specific tissues in the lung, spleen, and testis. TNF-alpha is increased in the lung in many forms of pu lmonary disease. In the current study, Western analysis, immunohistochemist ry, and ribonuclease protection assays were used to determine whether TNF-a lpha regulates the expression of these TNFR-associated proteins in lung cel ls. We demonstrate for the first time TNF-alpha dose-dependent induction of TRAF1 protein and messenger RNA (mRNA) in human H441 and A549 pulmonary ad enocarcinoma cell lines, as well as in lung cells of C57BL/6J mice after in tratracheal administration of TNF-alpha. In contrast to the epithelial cell s, TRAF1 was not induced by TNF-alpha in U937 cells, a human monocytic cell line, suggesting cell type-specific regulation. Similarly, cIAP2 mRNA was induced by TNF-alpha in both H441 and A549 pulmonary epithelial cells but n ot in U937 cells. TNF-alpha is a primary mediator of acute pulmonary inflam mation and contributes to the pathophysiology of chronic lung diseases such as bronchopulmonary dysplasia (BPD), a fibrotic disease of prematurely bor n infants. Immunohistochemical staining of human neonatal lung tissue demon strated increased TRAF1 in lungs of infants dying of pneumonia or BPD in co mparison with those dying of congenital malformation. These studies support the hypothesis that the TRAF1 and cIAP2 genes are highly regulated in pulm onary cells and may play a role in human lung disease.