STIMULATORY AND INHIBITORY EFFECTS OF INTERLEUKIN (IL)-4 AND IL-13 ONTHE PRODUCTION OF CYTOKINES BY HUMAN PERIPHERAL-BLOOD MONONUCLEAR-CELLS - PRIMING FOR IL-12 AND TUMOR-NECROSIS-FACTOR-ALPHA PRODUCTION

The production of cytokines in monocytes/macrophages is regulated by s everal different cytokines that have activating or inhibitory effects. Interleukin (IL)-10, IL-4, IL-13, and transforming growth factor (TGF )-beta are usually considered to be the most important macrophage-deac tivating factors, with inhibitory effects on cytokine production. Unli ke IL-10 and TGF-beta, which appear to act as downmodulators of many p hagocytic cell functions, the mode of action of IL-4 and IL-13 is more complex. Addition of IL-4 and IL-13 to peripheral blood mononuclear c ell (PBMC) cultures inhibited production of IL-12, tumor necrosis fact or (TNF)-alpha, IL-10, and IL-1 beta induced by lipopolysaccharide (LP S) or Staphylococcus aureus trs added simultaneously with the cytokine s. However, pretreatment of PBMC with IL-4 or IL-13 for greater than o r equal to 20 h enhanced the production of IL-12 and TNF-alpha in resp onse to LPS or S. aureus several fold in these cells; this IL-4-induce d priming for the two cytokines was inhibited by anti-IL-4 neutralizin g antibodies. IL-4 priming also enhanced the accumulation of IL-12 and TNF-alpha mRNA induced by LPS and S. aureus. The enhanced accumulatio n of transcripts for the IL-12 p35 and p40 chains by IL-4 priming was reflected in enhanced secretion of both the IL-12 free p40 chain and t he p70 heterodimer. These results suggest an unexpected complexity in the regulatory role of IL-4 and IL-13 in immune responses.