SPERMINE INHIBITS PROINFLAMMATORY CYTOKINE SYNTHESIS IN HUMAN MONONUCLEAR-CELLS - A COUNTERREGULATORY MECHANISM THAT RESTRAINS THE IMMUNE-RESPONSE

The local production of proinflammatory cytokines mediates the host re sponse to inflammation, infection, and injury, whereas an overexpressi on of these mediators can injure or kill the host. Recently, we identi fied a class of multivalent guanylhydrazone compounds that are effecti ve inhibitors of proinflammatory cytokine synthesis in monocytes/macro phages. The structure of one such cationic molecule suggested a molecu lar mimicry with spermine, a ubiquitous endogenous biogenic amine that increases significantly at sites of inflammation and infection. Here, we addressed the hypothesis that spermine might counter regulate the innate immune response by downregulating the synthesis of potentially injurious cytokines. When spermine was added to cultures of human peri pheral blood mononuclear cells stimulated with lipopolysaccharide (LPS ), it effectively inhibited the synthesis of the proinflammatory cytok ines tumor necrosis factor (TNF), interleukin-1 (IL-1), IL-6, MIP-1 al pha, and MIP-1 beta. The inhibition of cytokine synthesis was specific and reversible, with significant inhibition of TNF synthesis occurrin g even when spermine was added after LPS. The mechanism of spermine-me diated cytokine suppression was posttranscriptional and independent of polyamine oxidase activity. Local administration of spermine in vivo protected mice against the development of acute footpad inflammation i nduced by carrageenan. These results identify a distinct molecular cou nterregulatory role for spermine in downregulating the monocyte proinf lammatory cytokine response.