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By
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From the * Laboratory of Biomedical Science, Department of Surgery (Neurosurgery), North Shore
University Hospital, Manhasset, New York; the The local production of proinflammatory cytokines mediates the host response to inflammation, infection, and injury, whereas an overexpression of these mediators can injure or kill the
host. Recently, we identified a class of multivalent guanylhydrazone compounds that are effective
inhibitors of proinflammatory cytokine synthesis in monocytes/macrophages. The structure of
one such cationic molecule suggested a molecular 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 counterregulate the innate immune response
by downregulating the synthesis of potentially injurious cytokines. When spermine was added
to cultures of human peripheral blood mononuclear cells stimulated with lipopolysaccharide
(LPS), it effectively inhibited the synthesis of the proinflammatory cytokines tumor necrosis
factor (TNF), interleukin-1 (IL-1), IL-6, MIP-1 Department of Emergency Medicine, North Shore
University Hospital, Manhasset, New York; and § The Picower Institute for Medical Research,
Manhasset, New York
, and MIP-1
. The inhibition of cytokine
synthesis was specific and reversible, with significant inhibition of TNF synthesis occurring even when spermine was added after LPS. The mechanism of spermine-mediated 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 induced by carrageenan. These results identify a distinct molecular counterregulatory role for spermine in downregulating the monocyte proinflammatory cytokine response.
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