Heme oxygenase-1 mediates the anti-inflammatory effect of interleukin-10 in mice

Nat Med. 2002 Mar;8(3):240-6. doi: 10.1038/nm0302-240.

Abstract

The mechanisms underlying the action of the potent anti-inflammatory interleukin-10 (IL-10) are poorly understood. Here we show that, in murine macrophages, IL-10 induces expression of heme oxygenase-1 (HO-1), a stress-inducible protein with potential anti-inflammatory effect, via a p38 mitogen-activated protein kinase-dependent pathway. Inhibition of HO-1 protein synthesis or activity significantly reversed the inhibitory effect of IL-10 on production of tumor necrosis factor-alpha induced by lipopolysaccharide (LPS). Additional experiments revealed the involvement of carbon monoxide, one of the products of HO-1-mediated heme degradation, in the anti-inflammatory effect of IL-10 in vitro. Induction of HO-1 by IL-10 was also evident in vivo. IL-10-mediated protection against LPS-induced septic shock in mice was significantly attenuated by cotreatment with the HO inhibitor, zinc protoporphyrin. The identification of HO-1 as a downstream effector of IL-10 provides new possibilities for improved therapeutic approaches for treating inflammatory diseases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Inflammatory Agents / metabolism*
  • Cells, Cultured
  • Enzyme Activation
  • Enzyme Induction
  • Enzyme Inhibitors / pharmacology
  • Heme Oxygenase (Decyclizing) / antagonists & inhibitors
  • Heme Oxygenase (Decyclizing) / genetics*
  • Heme Oxygenase (Decyclizing) / metabolism*
  • Heme Oxygenase-1
  • Humans
  • Interleukin-10 / pharmacology
  • Interleukin-10 / physiology*
  • Interleukin-6 / pharmacology
  • Lipopolysaccharides / pharmacology
  • Macrophages, Peritoneal / drug effects
  • Macrophages, Peritoneal / physiology*
  • Male
  • Matrix Metalloproteinase 9 / metabolism
  • Membrane Proteins
  • Mice
  • Mice, Inbred BALB C
  • Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • Mitogen-Activated Protein Kinases / metabolism
  • Nitric Oxide Synthase / genetics
  • Nitric Oxide Synthase / metabolism
  • Nitric Oxide Synthase Type II
  • Oligodeoxyribonucleotides, Antisense / metabolism
  • Proteins / metabolism
  • Protoporphyrins / pharmacology
  • Repressor Proteins*
  • Signal Transduction
  • Suppressor of Cytokine Signaling 3 Protein
  • Suppressor of Cytokine Signaling Proteins
  • Transcription Factors*
  • Tumor Necrosis Factor-alpha / metabolism
  • p38 Mitogen-Activated Protein Kinases

Substances

  • Anti-Inflammatory Agents
  • Enzyme Inhibitors
  • Interleukin-6
  • Lipopolysaccharides
  • Membrane Proteins
  • Oligodeoxyribonucleotides, Antisense
  • Proteins
  • Protoporphyrins
  • Repressor Proteins
  • SOCS3 protein, human
  • Socs3 protein, mouse
  • Suppressor of Cytokine Signaling 3 Protein
  • Suppressor of Cytokine Signaling Proteins
  • Transcription Factors
  • Tumor Necrosis Factor-alpha
  • Interleukin-10
  • zinc protoporphyrin
  • NOS2 protein, human
  • Nitric Oxide Synthase
  • Nitric Oxide Synthase Type II
  • Nos2 protein, mouse
  • HMOX1 protein, human
  • Heme Oxygenase (Decyclizing)
  • Heme Oxygenase-1
  • Hmox1 protein, mouse
  • Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases
  • Matrix Metalloproteinase 9