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Spermine Inhibition of Monocyte Activation and Inflammation

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Abstract

The innate immune system functions as a defensive front line against pathogenic invasion, but the proinflammatory products of activated monocytes and macrophages (e.g., TNF and NO) can also injure normal cells. Anti-inflammatory mediators restrain the innate immune response and prevent excessive collateral tissue damage. Spermine, a ubiquitous biogenic polyamine, specifically and reversibly suppresses the synthesis of monocyte proinflammatory cytokines. This may provide a counterregulatory mechanism to restrain monocyte activation in injured or infected tissues and in tumors where spermine levels are significantly increased. Here we show that monocyte spermine uptake was significantly increased following lipopolysaccharide stimulation. The polyamine analogue l,4-bis(3-aminopropyl)-piperazine (BAP) inhibited LPS-stimulated monocyte spermine uptake via the “nonselective” polyamine transporter. BAP fully restored macrophage TNF synthesis despite the presence of spermine, indicating that the mechanism of monocyte deactivation by spermine is dependent on spermine uptake. Administration of BAP in vivo significantly augmented the development of carrageenan-induced paw edema and nitric oxide release. Thus, endogenous spermine normally inhibits the innate inflammatory response by restraining macrophages.

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Authors and Affiliations

  1. The Picower Institute for Medical Research, 350 Community Drive, Fourth Floor, Manhasset, New York, 11030, USA

    Minghuang Zhang, Lyudmila V. Borovikova, Haichao Wang, Christine Metz & Kevin J. Tracey

  2. Department of Emergency Medicine, North Shore University Hospital, Manhasset, New York, USA

    Haichao Wang

  3. Department of Surgery, North Shore University Hospital, Manhasset, New York, USA

    Kevin J. Tracey

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  1. Minghuang Zhang
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  2. Lyudmila V. Borovikova
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  4. Christine Metz
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  5. Kevin J. Tracey
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Correspondence to Minghuang Zhang.

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Zhang, M., Borovikova, L.V., Wang, H. et al. Spermine Inhibition of Monocyte Activation and Inflammation. Mol Med 5, 595–605 (1999). https://doi.org/10.1007/BF03402072

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