Globin attenuates the innate immune response to endotoxin

Huan Yang, Haichao Wang, Thomas R. Bernik, Svetlana Ivanova, Hong Wang, Luis Ulloa, Jesse Roth, John W. Eaton, Kevin J. Tracey

Research output: Contribution to journalArticlepeer-review

28 Scopus citations

Abstract

Hemoglobin is an endotoxin (lipopolysaccharide; LPS)-binding protein that synergistically increases the release of proinflammatory cytokines from the innate immune system in response to LPS. It has been suggested that this activity of hemoglobin facilitates the recognition of Gram-negative bacteria in a wound, thereby maximizing immune efficiency. This synergy may be important to the pathogenesis of a broad spectrum of clinical conditions because elevated hemoglobin levels frequently are observed in patients after the transfusion of red cells, trauma, cardiopulmonary bypass surgery, hemolysis, in addition to other disorders. To determine the molecular basis of the specific hemoglobin-LPS synergy, in this article we tested the effects of globin itself on macrophage responses to LPS. Paradoxically, these studies revealed that globin suppressed tumor necrosis factor (TNF) synthesis in LPS-stimulated murine and human macrophage cultures. LPS comigrated with globin on non-denaturing electrophoretic gels, giving direct evidence for binding. Globin specifically inhibited LPS activity in the standard Limulus assay but did not inhibit interleukin-1 β-mediated TNF synthesis. Iron supplementation of macrophage cultures significantly increased interleukin-1 β-induced TNF release. Intraperitoneal administration of globin protected mice against both LPS-induced lethality and experimentally induced bacterial infection. Thus, the heme-iron moiety of hemoglobin, and not the binding of LPS to globin, enhanced macrophage responses to LPS.

Original languageEnglish (US)
Pages (from-to)485-490
Number of pages6
JournalShock
Volume17
Issue number6
DOIs
StatePublished - Jun 2002
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Emergency Medicine
  • Critical Care and Intensive Care Medicine

Keywords

  • Cytokine
  • Hemoglobin
  • Lipopolysaccharide
  • Macrophage
  • Sepsis
  • Tumor necrosis factor

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