Heparin and enoxaparin enhance endotoxin-induced tumor necrosis factor- α production in human monocytes

Michael Heinzelmann, Marianne Miller, Andreas Platz, Laura E. Gordon, Daniel O. Herzig, Hiram C. Polk

Research output: Contribution to journalArticle

30 Scopus citations

Abstract

Objective: To determine whether heparin or the low-molecular-weight heparin enoxaparin alter lipopolysaccharide (LPS)-induced monocyte activation. Summary Background Data: Heparin is widely used in clinical practice to inhibit the coagulation cascade. However, heparin also is a naturally occurring glucosaminoglycan and a pleiotropic immunomodulator that binds to a variety of proteins. LPS is a component of gram-negative bacteria and is thought to be responsible for many of the deleterious effects seen in sepsis. The binding of LPS to CD14 induces a signaling cascade that results in the release of many inflammatory mediators, including tumor necrosis factor-alpha (TNF-α). Methods: Monocytes from healthy volunteers were isolated and cultured in the presence of saline, LPS (10 ng/ml), heparin (0.1 to 1000 μg/ml), or enoxaparin (0.1 to 1000 μg/ml). In blocking experiments, cells were pretreated for 60 minutes with the monoclonal anti-CD14 antibody MY4 (10 μg/ml) or with isotype-matched control IgG2 (10 μg/ml). TNF-α values were measured with enzyme-linked immunosorbent assay. Significance was assessed with analysis of variance. Results: Heparin (10 to 1000 μg/ml) and enoxaparin (1000 μg/ml) significantly enhanced LPS-induced TNF-α release. Heparin (1000 μg/ml) or enoxaparin (1000 μg/ml) did not produce TNF-α in the absence of LPS. Blockade of CD14 abrogated both LPS-induced TNF-α release and the effect of heparin or enoxaparin to enhance LPS-induced TNF-α release. Conclusions: The effect of heparin to enhance LPS-induced TNF-α release is a biologic phenomenon that reveals a novel and potentially important host defense mechanism during endotoxemia and sepsis. Binding of LPS to CD14 is necessary to induce this phenomenon, suggesting that both heparin and enoxaparin induce signaling mechanisms that are downstream from the initial binding of LPS on CD14.

Original languageEnglish (US)
Pages (from-to)542-550
Number of pages9
JournalAnnals of surgery
Volume229
Issue number4
DOIs
StatePublished - Apr 1 1999

ASJC Scopus subject areas

  • Surgery

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