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
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Anti-Inflammatory Agents / metabolism*
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Cells, Cultured
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Enzyme Activation
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Enzyme Induction
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Enzyme Inhibitors / pharmacology
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Heme Oxygenase (Decyclizing) / antagonists & inhibitors
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Heme Oxygenase (Decyclizing) / genetics*
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Heme Oxygenase (Decyclizing) / metabolism*
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Heme Oxygenase-1
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Humans
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Interleukin-10 / pharmacology
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Interleukin-10 / physiology*
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Interleukin-6 / pharmacology
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Lipopolysaccharides / pharmacology
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Macrophages, Peritoneal / drug effects
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Macrophages, Peritoneal / physiology*
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Male
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Matrix Metalloproteinase 9 / metabolism
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Membrane Proteins
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Mice
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Mice, Inbred BALB C
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Mitogen-Activated Protein Kinases / antagonists & inhibitors
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Mitogen-Activated Protein Kinases / metabolism
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Nitric Oxide Synthase / genetics
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Nitric Oxide Synthase / metabolism
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Nitric Oxide Synthase Type II
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Oligodeoxyribonucleotides, Antisense / metabolism
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Proteins / metabolism
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Protoporphyrins / pharmacology
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Repressor Proteins*
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Signal Transduction
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Suppressor of Cytokine Signaling 3 Protein
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Suppressor of Cytokine Signaling Proteins
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Transcription Factors*
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Tumor Necrosis Factor-alpha / metabolism
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p38 Mitogen-Activated Protein Kinases
Substances
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Anti-Inflammatory Agents
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Enzyme Inhibitors
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Interleukin-6
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Lipopolysaccharides
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Membrane Proteins
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Oligodeoxyribonucleotides, Antisense
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Proteins
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Protoporphyrins
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Repressor Proteins
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SOCS3 protein, human
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Socs3 protein, mouse
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Suppressor of Cytokine Signaling 3 Protein
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Suppressor of Cytokine Signaling Proteins
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Transcription Factors
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Tumor Necrosis Factor-alpha
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Interleukin-10
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zinc protoporphyrin
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NOS2 protein, human
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Nitric Oxide Synthase
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Nitric Oxide Synthase Type II
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Nos2 protein, mouse
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HMOX1 protein, human
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Heme Oxygenase (Decyclizing)
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Heme Oxygenase-1
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Hmox1 protein, mouse
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Mitogen-Activated Protein Kinases
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p38 Mitogen-Activated Protein Kinases
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Matrix Metalloproteinase 9