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

Nature Medicine volume 8, pages 240–246 (2002)Cite this article

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-α 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.

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Figure 1: IL-10 induces HO-1 protein expression in murine macrophages.
Figure 2: Involvement of p38 activation in IL-10-induced HO-1 gene expression.
Figure 3: HO-1 mediates IL-10-induced suppression of TNF-α production in LPS-activated J774 cells.
Figure 4: HO-1 inhibition reverses IL-10-induced suppression of TNF-α production in LPS-activated primary macrophages.
Figure 5: HO-1 mediates IL-10-induced suppression of NO production and MMP-9 expression.
Figure 6: HO-1 is essential for IL-10-mediated protection against LPS-induced septic shock.

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Acknowledgements

This work was supported by grants from the National Science Council of Taiwan (NSC-90-2320-B-001-039) and the Institute of Biomedical Sciences, Academia Sinica, Taiwan, ROC.

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  1. Graduate Institute of Life Sciences, National Defense Medical Center, and Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan, Republic of China

    Tzong-Shyuan Lee & Lee-Young Chau

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Correspondence to Lee-Young Chau.

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Lee, TS., Chau, LY. Heme oxygenase-1 mediates the anti-inflammatory effect of interleukin-10 in mice. Nat Med 8, 240–246 (2002). https://doi.org/10.1038/nm0302-240

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