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-1α, 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.
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19 May 1997
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May 19 1997
Spermine Inhibits Proinflammatory Cytokine Synthesis in Human Mononuclear Cells: A Counterregulatory Mechanism that Restrains the Immune Response
Minghuang Zhang,
Minghuang Zhang
From the *Laboratory of Biomedical Science, Department of Surgery (Neurosurgery), North Shore University Hospital, Manhasset, New York; the ‡Department of Emergency Medicine, North Shore University Hospital, Manhasset, New York; and §The Picower Institute for Medical Research, Manhasset, New York
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Theresa Caragine,
Theresa Caragine
From the *Laboratory of Biomedical Science, Department of Surgery (Neurosurgery), North Shore University Hospital, Manhasset, New York; the ‡Department of Emergency Medicine, North Shore University Hospital, Manhasset, New York; and §The Picower Institute for Medical Research, Manhasset, New York
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Haichao Wang,
Haichao Wang
From the *Laboratory of Biomedical Science, Department of Surgery (Neurosurgery), North Shore University Hospital, Manhasset, New York; the ‡Department of Emergency Medicine, North Shore University Hospital, Manhasset, New York; and §The Picower Institute for Medical Research, Manhasset, New York
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Pamela S. Cohen,
Pamela S. Cohen
From the *Laboratory of Biomedical Science, Department of Surgery (Neurosurgery), North Shore University Hospital, Manhasset, New York; the ‡Department of Emergency Medicine, North Shore University Hospital, Manhasset, New York; and §The Picower Institute for Medical Research, Manhasset, New York
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Galina Botchkina,
Galina Botchkina
From the *Laboratory of Biomedical Science, Department of Surgery (Neurosurgery), North Shore University Hospital, Manhasset, New York; the ‡Department of Emergency Medicine, North Shore University Hospital, Manhasset, New York; and §The Picower Institute for Medical Research, Manhasset, New York
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Kuniyasu Soda,
Kuniyasu Soda
From the *Laboratory of Biomedical Science, Department of Surgery (Neurosurgery), North Shore University Hospital, Manhasset, New York; the ‡Department of Emergency Medicine, North Shore University Hospital, Manhasset, New York; and §The Picower Institute for Medical Research, Manhasset, New York
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Marina Bianchi,
Marina Bianchi
From the *Laboratory of Biomedical Science, Department of Surgery (Neurosurgery), North Shore University Hospital, Manhasset, New York; the ‡Department of Emergency Medicine, North Shore University Hospital, Manhasset, New York; and §The Picower Institute for Medical Research, Manhasset, New York
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Peter Ulrich,
Peter Ulrich
From the *Laboratory of Biomedical Science, Department of Surgery (Neurosurgery), North Shore University Hospital, Manhasset, New York; the ‡Department of Emergency Medicine, North Shore University Hospital, Manhasset, New York; and §The Picower Institute for Medical Research, Manhasset, New York
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Anthony Cerami,
Anthony Cerami
From the *Laboratory of Biomedical Science, Department of Surgery (Neurosurgery), North Shore University Hospital, Manhasset, New York; the ‡Department of Emergency Medicine, North Shore University Hospital, Manhasset, New York; and §The Picower Institute for Medical Research, Manhasset, New York
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Barbara Sherry,
Barbara Sherry
From the *Laboratory of Biomedical Science, Department of Surgery (Neurosurgery), North Shore University Hospital, Manhasset, New York; the ‡Department of Emergency Medicine, North Shore University Hospital, Manhasset, New York; and §The Picower Institute for Medical Research, Manhasset, New York
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Kevin J. Tracey
Kevin J. Tracey
From the *Laboratory of Biomedical Science, Department of Surgery (Neurosurgery), North Shore University Hospital, Manhasset, New York; the ‡Department of Emergency Medicine, North Shore University Hospital, Manhasset, New York; and §The Picower Institute for Medical Research, Manhasset, New York
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Minghuang Zhang
From the *Laboratory of Biomedical Science, Department of Surgery (Neurosurgery), North Shore University Hospital, Manhasset, New York; the ‡Department of Emergency Medicine, North Shore University Hospital, Manhasset, New York; and §The Picower Institute for Medical Research, Manhasset, New York
Theresa Caragine
From the *Laboratory of Biomedical Science, Department of Surgery (Neurosurgery), North Shore University Hospital, Manhasset, New York; the ‡Department of Emergency Medicine, North Shore University Hospital, Manhasset, New York; and §The Picower Institute for Medical Research, Manhasset, New York
Haichao Wang
From the *Laboratory of Biomedical Science, Department of Surgery (Neurosurgery), North Shore University Hospital, Manhasset, New York; the ‡Department of Emergency Medicine, North Shore University Hospital, Manhasset, New York; and §The Picower Institute for Medical Research, Manhasset, New York
Pamela S. Cohen
From the *Laboratory of Biomedical Science, Department of Surgery (Neurosurgery), North Shore University Hospital, Manhasset, New York; the ‡Department of Emergency Medicine, North Shore University Hospital, Manhasset, New York; and §The Picower Institute for Medical Research, Manhasset, New York
Galina Botchkina
From the *Laboratory of Biomedical Science, Department of Surgery (Neurosurgery), North Shore University Hospital, Manhasset, New York; the ‡Department of Emergency Medicine, North Shore University Hospital, Manhasset, New York; and §The Picower Institute for Medical Research, Manhasset, New York
Kuniyasu Soda
From the *Laboratory of Biomedical Science, Department of Surgery (Neurosurgery), North Shore University Hospital, Manhasset, New York; the ‡Department of Emergency Medicine, North Shore University Hospital, Manhasset, New York; and §The Picower Institute for Medical Research, Manhasset, New York
Marina Bianchi
From the *Laboratory of Biomedical Science, Department of Surgery (Neurosurgery), North Shore University Hospital, Manhasset, New York; the ‡Department of Emergency Medicine, North Shore University Hospital, Manhasset, New York; and §The Picower Institute for Medical Research, Manhasset, New York
Peter Ulrich
From the *Laboratory of Biomedical Science, Department of Surgery (Neurosurgery), North Shore University Hospital, Manhasset, New York; the ‡Department of Emergency Medicine, North Shore University Hospital, Manhasset, New York; and §The Picower Institute for Medical Research, Manhasset, New York
Anthony Cerami
From the *Laboratory of Biomedical Science, Department of Surgery (Neurosurgery), North Shore University Hospital, Manhasset, New York; the ‡Department of Emergency Medicine, North Shore University Hospital, Manhasset, New York; and §The Picower Institute for Medical Research, Manhasset, New York
Barbara Sherry
From the *Laboratory of Biomedical Science, Department of Surgery (Neurosurgery), North Shore University Hospital, Manhasset, New York; the ‡Department of Emergency Medicine, North Shore University Hospital, Manhasset, New York; and §The Picower Institute for Medical Research, Manhasset, New York
Kevin J. Tracey
From the *Laboratory of Biomedical Science, Department of Surgery (Neurosurgery), North Shore University Hospital, Manhasset, New York; the ‡Department of Emergency Medicine, North Shore University Hospital, Manhasset, New York; and §The Picower Institute for Medical Research, Manhasset, New York
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.
Received:
December 16 1996
Revision Received:
February 28 1997
Online ISSN: 1540-9538
Print ISSN: 0022-1007
1997
J Exp Med (1997) 185 (10): 1759–1768.
Article history
Received:
December 16 1996
Revision Received:
February 28 1997
Citation
Minghuang Zhang, Theresa Caragine, Haichao Wang, Pamela S. Cohen, Galina Botchkina, Kuniyasu Soda, Marina Bianchi, Peter Ulrich, Anthony Cerami, Barbara Sherry, Kevin J. Tracey; Spermine Inhibits Proinflammatory Cytokine Synthesis in Human Mononuclear Cells: A Counterregulatory Mechanism that Restrains the Immune Response. J Exp Med 19 May 1997; 185 (10): 1759–1768. doi: https://doi.org/10.1084/jem.185.10.1759
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