The Journal of Experimental Medicine
VeriKine-HS Human IFN-Beta
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© The Rockefeller University Press, 0022-1007/1997/5/1759/ $5.00
The Journal of Experimental Medicine, Volume 185, Number 10, May 19, 1997 1759-1768


Articles

Spermine Inhibits Proinflammatory Cytokine Synthesis in Human Mononuclear Cells: A Counterregulatory Mechanism that Restrains the Immune Response

Minghuang Zhang§, Theresa Caragine§, Haichao Wang{ddagger},§, Pamela S. Cohen§, Galina Botchkina§, Kuniyasu Soda§, Marina Bianchi§, Peter Ulrich§, Anthony Cerami§, Barbara Sherry§, and Kevin J. Tracey*,§

From the * Laboratory of Biomedical Science, Department of Surgery (Neurosurgery), North Shore University Hospital, Manhasset, New York; the {ddagger} Department of Emergency Medicine, North Shore University Hospital, Manhasset, New York; and § The Picower Institute for Medical Research, Manhasset, New York

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{alpha}, and MIP-1β. 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.


Address correspondence to Kevin J. Tracey, North Shore University Hospital, The Picower Institute for Medical Research, 350 Community Drive, Manhasset, NY 11030.

1 Abbreviations used in this paper: iNOS, inducible nitric oxide synthase; LDH, lactate dehydrogenase; NO, nitric oxide; PKC, protein kinase C.


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