The effects of a Th1-cell-associated cytokine (interferon-gamma [IFN-gamma]) and Th2-cell-associated cytokines (interleukin [IL]-4, IL-10, and IL-13) on prostaglandin (PG) production by human alveolar macrophages (AM) were examined in terms of four parameters: PGE2 synthesis, cyclooxygenase (COX) activity, and the protein and mRNA of two COX isozymes (COX-1 and COX-2). Lipopolysaccharide (LPS)-stimulated PGE2 synthesis and COX activity were suppressed significantly by IL-4, but were not affected significantly by IL-10, IL-13, or IFN-gamma. The LPS-dependent increase in COX activity in AM was attributable to COX-2 because it was inhibited by NS-398 (a COX-2-specific inhibitor). Western and Northern blot analyses revealed that the LPS-induced increases in COX-2 protein and mRNA were attenuated by IL-4 but hardly affected by IL-10, IL-13 or IFN-gamma. In contrast, COX-1 protein and mRNA were hardly detected in any of the AM preparations. In AM and monocytes from the same individuals, LPS induced the synthesis of large amounts of PGE2 and COX-2 mRNA in AM, and of lesser amounts in monocytes. IL-4, IL-10, and IL-13 significantly suppressed LPS-dependent PGE2 synthesis and COX-2 mRNA induction in monocytes, whereas only IL-4 significantly suppressed them in AM. Furthermore, 15-lipoxygenase mRNA was detectable only in monocytes incubated with LPS plus IL-4. These results suggest that IL-4 is a potent regulator of PG production in AM, and that regulation of the arachidonic-acid (AA) metabolic pathway in cells of monocyte-macrophage lineage by Th2-cell-associated cytokines depends on the stage of cell differentiation.