To investigate whether antigen-independent, interleukin-2 (IL-2) or IL-15 activation of polarized T helper (Th) cells would result in contact-dependent activation of monocytes, living Th1 and Th2 cell clones were co-cultured with THP-1 cells or fresh peripheral blood monocytes. Under these conditions IL-1beta production was induced almost exclusively by Th1 cells and was dependent on the presence and dose of IL-2 or IL-15, and on cell-cell contact, as demonstrated by double-chamber cultures. Low levels of IL-1 receptor antagonist (IL-1Ra) were induced by Th1 and higher levels by Th2 cells. IL-10 production was similar in Th1/monocyte and Th2/monocyte co-cultures, thus arguing against preferential down-regulation of IL-1beta production by anti-inflammatory IL-10 in Th2 co-cultures. In addition, IL-4 and IL-10 neutralization did not result in enhanced IL-1beta production in Th2/monocyte co-cultures. Preferential expression on Th1 cells of CD11b correlated with their capacity to induce IL-1beta production by THP-1 cells in the presence of IL-2 or IL-15, but anti-CD11b monoclonal antibody could not inhibit this activity. Blockade of the CD40-CD40 ligand interaction resulted in inhibition of IL-1beta-inducing capacity while IL-1Ra induction was unaffected, a result previously unknown. This differential effect indicates the selective relevance of CD40-CD40 ligand engagement in inflammatory monocyte responses upon activation by T cells. CD40 ligand expression levels did not differ in Th1 and Th2 cell clones, thus indicating that additional, unidentified molecule(s) preferentially expressed by Th1 cells are involved in their IL-1beta induction capacity.