Heme oxygenase-1 mediates the anti-inflammatory effect of interleukin-10 in mice.
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.
Lee
Tzong-Shyuan
TS
Graduate Institute of Life Sciences, National Defense Medical Center, and Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan, Republic of China.
Chau
Lee-Young
LY
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000378:metabolism*; D002478:Cells, Cultured; D004789:Enzyme Activation; D004790:Enzyme Induction; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006419:Heme Oxygenase (Decyclizing) / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D051547:Heme Oxygenase-1; D006801:Humans; D016753:Interleukin-10 / Q000494:pharmacology / Q000502:physiology*; D015850:Interleukin-6 / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000502:physiology*; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008565:Membrane Proteins; D051379:Mice; D008807:Mice, Inbred BALB C; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D020319:Oligodeoxyribonucleotides, Antisense / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D011524:Protoporphyrins / Q000494:pharmacology; D012097:Repressor Proteins; D015398:Signal Transduction; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases
D000893:Anti-Inflammatory Agents; D004791:Enzyme Inhibitors; D015850:Interleukin-6; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D020319:Oligodeoxyribonucleotides, Antisense; D011506:Proteins; D011524:Protoporphyrins; D012097:Repressor Proteins; C106644:SOCS3 protein, human; C491411:Socs3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; C017803:zinc protoporphyrin; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C496541:HMOX1 protein, human; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D020780:Matrix Metalloproteinase 9