Spermine differentially regulates the production of interleukin-12 p40 andinterleukin-10 and suppresses the release of the T helper 1 cytokine interferon-gamma

Polyamines are endogenous immunomodulatory molecules. Recent studies reveal ed that polyamines suppress the production of proinflammatory cytokines and nitric oxide. In the present study, we investigated the effect of the poly amines spermine, spermidine, and putrescine on the production of interleuki n (IL)-12 p40, IL-10, and interferon (IFN-gamma) in mouse peritoneal macrop hages and spleen cell suspensions. Spermine, but not spermidine or putresci ne, suppressed, in a concentration-dependent manner, the production of IL-1 2 p40 by lipopolysaccharide (LPS)-stimulated macrophages. The effect of spe rmine was post-transcriptional, because steady-state levels of messenger ri bonucleic acid (mRNAs) for IL-12 (p35 and p40) were not affected. In contra st to its inhibitory effect on IL-12 p40, spermine (0.3-3 CIM) augmented IL -10 production. The down-regulation of IL-12 p40 by spermine was independen t of enhancement of IL-10 by this agent, for spermine retained its ability to suppress IL-12 production in peritoneal macrophages obtained from IL-10- deficient mice. The alterations in cytokine production by spermine did not involve an effect on early intracellular pathways of LPS signal transductio n, including the p38 or p42/44 mitogen-activated protein kinases, or the c- jun terminal kinase. In spleen cell suspensions, spermine suppressed the re lease of IFN-gamma induced either by LPS or anti-CD3 antibody. In summary, spermine exerts anti-inflammatory effects by suppressing IL-12 and IFN-gamm a and by augmenting the production of IL-10.