Effect of taxol and taxotere on gene expression in macrophages: Induction of the prostaglandin H synthase-2 isoenzyme

Induction of genes encoding cytokines or other, unidentified proteins may c ontribute to the pharmacological effects of taxol. We hypothesized that pro staglandin 11 synthase-2 (PGHS-2) was one of the unidentified genes induced by taxol. Taxol alone or taxol plus IFN-gamma increased PGE(2) formation, PGHS-2 protein expression, and PGHS-2 mRNA expression in RAW 264.7 murine m acrophages. The kinetics for mRNA induction, protein expression, and cataly sis were self-consistent. A selective inhibitor of PGHS-2 blocked PGE(2) fo rmation by cells incubated with taxol; a selective inhibitor of PGHS-1 had no effect. A glucocorticoid blocked the induction of mRNA, the expression o f PGHS-2 protein, and the formation of PGE(2). Neither taxol alone nor taxo l plus IFN-gamma altered the expression of the PGHS-1 isoenzyme in RAW 264. 7 cells. Taxotere, an analogue that stabilizes microtubules as potently as taxol, did not alter the expression of PGHS-2, implying that its induction in RAW 264.7 murine macrophages did not originate from microtubule stabiliz ation. Taxol and taxotere each induced PGHS-2 expression in human monocytes suspended in 10% human serum. However, human monocytes suspended in 10% bo vine serum responded only to LPS; not to taxol or taxotere, implying that t hey act independently of the LPS-mimetic process that is prominent in mice. Taxol induced PGHS-2 in human and murine monocytes via a p38 mitogen-assoc iated protein kinase pathway. The inclusion of PGHS-2 among the early respo nse genes induced in leukocytes may be relevant to the beneficial and adver se effects encountered during taxol administration.