Tumor necrosis factor-alpha is known to upregulate the expression of surface adhesion molecules on polymorphonuclear leukocytes (PMNs). The purpose of this investigation was to study possible intracellular signaling pathways responsible for the upregulation of beta 2 integrins on normal human PMNs induced by TNF. We report that treatment with TNF (10 ng/ml) for 30 min resulted in a significant increase in CD18 and MAC-1 surface expression (P < 0.001). In addition, pretreatment with 15 mu M SB203580, a p38 MAP kinase inhibitor, for 10 min significantly inhibited TNF upregulation of CD18 and MAC-1 (P < 0.0001). Pretreatment with either 15 mu M PD 98059, a p42/44 MAP kinase inhibitor, or 5 mu M GO 6850, a protein kinase C inhibitor, had no significant inhibitory effect. These data suggest that the TNF-induced upregulation of beta 2 integrins is mediated specifically through the p38 MAP kinase pathway and not through the p42/44 MAP kinase or protein kinase C pathways.