Skip to main content
NCBI home page
Biochemical Journal logoLink to Biochemical Journal
. 2001 Feb 1;353(Pt 3):459–466. doi: 10.1042/0264-6021:3530459

Haem oxygenase-1: a novel player in cutaneous wound repair and psoriasis?

C Hanselmann 1, C Mauch 1, S Werner 1
PMCID: PMC1221590  PMID: 11171041

Abstract

Haem oxygenase (HO) is the rate-limiting enzyme in the degradation of haem. In addition to its obvious role in iron metabolism, a series of findings indicate an important role for HO in cellular protection against oxidative stress. This effect might be of particular importance during wound healing and also in inflammatory disease. Therefore we determined the expression of the two HO isoenzymes, HO-1 and HO-2, during the healing process of full-thickness excisional wounds in mice. We show a remarkable induction of HO-1 mRNA and protein expression within three days after skin injury. After completion of wound healing, HO-1 expression declined to basal levels. By contrast, expression of HO-2 was not significantly modulated by skin injury. In situ hybridization and immunohistochemistry revealed high HO-1 expression in inflammatory cells of the granulation tissue and in keratinocytes of the hyperproliferative epithelium. A strong overexpression of HO-1 was also observed in the skin of patients suffering from the inflammatory skin disease psoriasis. In addition, HO-2 mRNA levels were increased in the skin of psoriatic patients. Similar to wounded skin, inflammatory cells and keratinocytes of the hyperthickened epidermis were the major producers of HO-1 in psoriatic skin. In vitro studies with cultured keratinocytes revealed a potential role for reactive oxygen species (ROS), but not for growth factors and pro-inflammatory cytokines, as inducers of HO-1 expression in inflamed skin. Our findings suggest a novel role for HO in wound healing and inflammatory skin disease, where it might be involved in haem degradation and in the protection of cells from the toxic effects of ROS.

Full Text

The Full Text of this article is available as a PDF (353.2 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Applegate L. A., Luscher P., Tyrrell R. M. Induction of heme oxygenase: a general response to oxidant stress in cultured mammalian cells. Cancer Res. 1991 Feb 1;51(3):974–978. [PubMed] [Google Scholar]
  2. Applegate L. A., Noël A., Vile G., Frenk E., Tyrrell R. M. Two genes contribute to different extents to the heme oxygenase enzyme activity measured in cultured human skin fibroblasts and keratinocytes: implications for protection against oxidant stress. Photochem Photobiol. 1995 Mar;61(3):285–291. doi: 10.1111/j.1751-1097.1995.tb03973.x. [DOI] [PubMed] [Google Scholar]
  3. Boukamp P., Petrussevska R. T., Breitkreutz D., Hornung J., Markham A., Fusenig N. E. Normal keratinization in a spontaneously immortalized aneuploid human keratinocyte cell line. J Cell Biol. 1988 Mar;106(3):761–771. doi: 10.1083/jcb.106.3.761. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Cerutti P. A., Trump B. F. Inflammation and oxidative stress in carcinogenesis. Cancer Cells. 1991 Jan;3(1):1–7. [PubMed] [Google Scholar]
  5. Choi A. M., Alam J. Heme oxygenase-1: function, regulation, and implication of a novel stress-inducible protein in oxidant-induced lung injury. Am J Respir Cell Mol Biol. 1996 Jul;15(1):9–19. doi: 10.1165/ajrcmb.15.1.8679227. [DOI] [PubMed] [Google Scholar]
  6. Chomczynski P., Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987 Apr;162(1):156–159. doi: 10.1006/abio.1987.9999. [DOI] [PubMed] [Google Scholar]
  7. Clark J. E., Green C. J., Motterlini R. Involvement of the heme oxygenase-carbon monoxide pathway in keratinocyte proliferation. Biochem Biophys Res Commun. 1997 Dec 18;241(2):215–220. doi: 10.1006/bbrc.1997.7742. [DOI] [PubMed] [Google Scholar]
  8. Dennery P. A., Spitz D. R., Yang G., Tatarov A., Lee C. S., Shegog M. L., Poss K. D. Oxygen toxicity and iron accumulation in the lungs of mice lacking heme oxygenase-2. J Clin Invest. 1998 Mar 1;101(5):1001–1011. doi: 10.1172/JCI448. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Dennery P. A., Sridhar K. J., Lee C. S., Wong H. E., Shokoohi V., Rodgers P. A., Spitz D. R. Heme oxygenase-mediated resistance to oxygen toxicity in hamster fibroblasts. J Biol Chem. 1997 Jun 6;272(23):14937–14942. doi: 10.1074/jbc.272.23.14937. [DOI] [PubMed] [Google Scholar]
  10. Dennery P. A., Wong H. E., Sridhar K. J., Rodgers P. A., Sim J. E., Spitz D. R. Differences in basal and hyperoxia-associated HO expression in oxidant-resistant hamster fibroblasts. Am J Physiol. 1996 Oct;271(4 Pt 1):L672–L679. doi: 10.1152/ajplung.1996.271.4.L672. [DOI] [PubMed] [Google Scholar]
  11. Dong Z., Lavrovsky Y., Venkatachalam M. A., Roy A. K. Heme oxygenase-1 in tissue pathology: the Yin and Yang. Am J Pathol. 2000 May;156(5):1485–1488. doi: 10.1016/S0002-9440(10)65019-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Elbirt K. K., Bonkovsky H. L. Heme oxygenase: recent advances in understanding its regulation and role. Proc Assoc Am Physicians. 1999 Sep-Oct;111(5):438–447. [PubMed] [Google Scholar]
  13. Elder J. T., Fisher G. J., Lindquist P. B., Bennett G. L., Pittelkow M. R., Coffey R. J., Jr, Ellingsworth L., Derynck R., Voorhees J. J. Overexpression of transforming growth factor alpha in psoriatic epidermis. Science. 1989 Feb 10;243(4892):811–814. doi: 10.1126/science.2916128. [DOI] [PubMed] [Google Scholar]
  14. Er-raki A., Charveron M., Bonafé J. L. Increased superoxide anion production in dermal fibroblasts of psoriatic patients. Skin Pharmacol. 1993;6(4):253–258. doi: 10.1159/000211146. [DOI] [PubMed] [Google Scholar]
  15. Ferris C. D., Jaffrey S. R., Sawa A., Takahashi M., Brady S. D., Barrow R. K., Tysoe S. A., Wolosker H., Barañano D. E., Doré S. Haem oxygenase-1 prevents cell death by regulating cellular iron. Nat Cell Biol. 1999 Jul;1(3):152–157. doi: 10.1038/11072. [DOI] [PubMed] [Google Scholar]
  16. Finch P. W., Murphy F., Cardinale I., Krueger J. G. Altered expression of keratinocyte growth factor and its receptor in psoriasis. Am J Pathol. 1997 Dec;151(6):1619–1628. [PMC free article] [PubMed] [Google Scholar]
  17. Foresti R., Motterlini R. The heme oxygenase pathway and its interaction with nitric oxide in the control of cellular homeostasis. Free Radic Res. 1999 Dec;31(6):459–475. doi: 10.1080/10715769900301031. [DOI] [PubMed] [Google Scholar]
  18. Frank S., Munz B., Werner S. The human homologue of a bovine non-selenium glutathione peroxidase is a novel keratinocyte growth factor-regulated gene. Oncogene. 1997 Feb 27;14(8):915–921. doi: 10.1038/sj.onc.1200905. [DOI] [PubMed] [Google Scholar]
  19. Fridovich I. The biology of oxygen radicals. Science. 1978 Sep 8;201(4359):875–880. doi: 10.1126/science.210504. [DOI] [PubMed] [Google Scholar]
  20. Ishii T., Itoh K., Sato H., Bannai S. Oxidative stress-inducible proteins in macrophages. Free Radic Res. 1999 Oct;31(4):351–355. doi: 10.1080/10715769900300921. [DOI] [PubMed] [Google Scholar]
  21. Kadunce D. P., Krueger G. G. Pathogenesis of psoriasis. Dermatol Clin. 1995 Oct;13(4):723–737. [PubMed] [Google Scholar]
  22. Lee P. J., Alam J., Wiegand G. W., Choi A. M. Overexpression of heme oxygenase-1 in human pulmonary epithelial cells results in cell growth arrest and increased resistance to hyperoxia. Proc Natl Acad Sci U S A. 1996 Sep 17;93(19):10393–10398. doi: 10.1073/pnas.93.19.10393. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Lee P. J., Jiang B. H., Chin B. Y., Iyer N. V., Alam J., Semenza G. L., Choi A. M. Hypoxia-inducible factor-1 mediates transcriptional activation of the heme oxygenase-1 gene in response to hypoxia. J Biol Chem. 1997 Feb 28;272(9):5375–5381. [PubMed] [Google Scholar]
  24. Löntz W., Sirsjö A., Liu W., Lindberg M., Rollman O., Törmä H. Increased mRNA expression of manganese superoxide dismutase in psoriasis skin lesions and in cultured human keratinocytes exposed to IL-1 beta and TNF-alpha. Free Radic Biol Med. 1995 Feb;18(2):349–355. doi: 10.1016/0891-5849(94)e0124-2. [DOI] [PubMed] [Google Scholar]
  25. Martin P. Wound healing--aiming for perfect skin regeneration. Science. 1997 Apr 4;276(5309):75–81. doi: 10.1126/science.276.5309.75. [DOI] [PubMed] [Google Scholar]
  26. Meier B., Radeke H. H., Selle S., Younes M., Sies H., Resch K., Habermehl G. G. Human fibroblasts release reactive oxygen species in response to interleukin-1 or tumour necrosis factor-alpha. Biochem J. 1989 Oct 15;263(2):539–545. doi: 10.1042/bj2630539. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Michiels C., Raes M., Toussaint O., Remacle J. Importance of Se-glutathione peroxidase, catalase, and Cu/Zn-SOD for cell survival against oxidative stress. Free Radic Biol Med. 1994 Sep;17(3):235–248. doi: 10.1016/0891-5849(94)90079-5. [DOI] [PubMed] [Google Scholar]
  28. Munz B., Frank S., Hübner G., Olsen E., Werner S. A novel type of glutathione peroxidase: expression and regulation during wound repair. Biochem J. 1997 Sep 1;326(Pt 2):579–585. doi: 10.1042/bj3260579. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. O'Toole E. A., Goel M., Woodley D. T. Hydrogen peroxide inhibits human keratinocyte migration. Dermatol Surg. 1996 Jun;22(6):525–529. doi: 10.1111/j.1524-4725.1996.tb00368.x. [DOI] [PubMed] [Google Scholar]
  30. Otterbein L. E., Bach F. H., Alam J., Soares M., Tao Lu H., Wysk M., Davis R. J., Flavell R. A., Choi A. M. Carbon monoxide has anti-inflammatory effects involving the mitogen-activated protein kinase pathway. Nat Med. 2000 Apr;6(4):422–428. doi: 10.1038/74680. [DOI] [PubMed] [Google Scholar]
  31. Poss K. D., Tonegawa S. Heme oxygenase 1 is required for mammalian iron reutilization. Proc Natl Acad Sci U S A. 1997 Sep 30;94(20):10919–10924. doi: 10.1073/pnas.94.20.10919. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Poss K. D., Tonegawa S. Reduced stress defense in heme oxygenase 1-deficient cells. Proc Natl Acad Sci U S A. 1997 Sep 30;94(20):10925–10930. doi: 10.1073/pnas.94.20.10925. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Shindo Y., Witt E., Han D., Epstein W., Packer L. Enzymic and non-enzymic antioxidants in epidermis and dermis of human skin. J Invest Dermatol. 1994 Jan;102(1):122–124. doi: 10.1111/1523-1747.ep12371744. [DOI] [PubMed] [Google Scholar]
  34. Shindo Y., Witt E., Packer L. Antioxidant defense mechanisms in murine epidermis and dermis and their responses to ultraviolet light. J Invest Dermatol. 1993 Mar;100(3):260–265. doi: 10.1111/1523-1747.ep12469048. [DOI] [PubMed] [Google Scholar]
  35. Steiling H., Munz B., Werner S., Brauchle M. Different types of ROS-scavenging enzymes are expressed during cutaneous wound repair. Exp Cell Res. 1999 Mar 15;247(2):484–494. doi: 10.1006/excr.1998.4366. [DOI] [PubMed] [Google Scholar]
  36. Stocker R., Yamamoto Y., McDonagh A. F., Glazer A. N., Ames B. N. Bilirubin is an antioxidant of possible physiological importance. Science. 1987 Feb 27;235(4792):1043–1046. doi: 10.1126/science.3029864. [DOI] [PubMed] [Google Scholar]
  37. Tenhunen R., Marver H. S., Schmid R. The enzymatic conversion of heme to bilirubin by microsomal heme oxygenase. Proc Natl Acad Sci U S A. 1968 Oct;61(2):748–755. doi: 10.1073/pnas.61.2.748. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Vessey D. A., Lee K. H., Blacker K. L. Characterization of the oxidative stress initiated in cultured human keratinocytes by treatment with peroxides. J Invest Dermatol. 1992 Dec;99(6):859–863. doi: 10.1111/1523-1747.ep12614831. [DOI] [PubMed] [Google Scholar]
  39. Vile G. F., Basu-Modak S., Waltner C., Tyrrell R. M. Heme oxygenase 1 mediates an adaptive response to oxidative stress in human skin fibroblasts. Proc Natl Acad Sci U S A. 1994 Mar 29;91(7):2607–2610. doi: 10.1073/pnas.91.7.2607. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Weller R. Nitric oxide, skin growth and differentiation: more questions than answers? Clin Exp Dermatol. 1999 Sep;24(5):388–391. doi: 10.1046/j.1365-2230.1999.00509.x. [DOI] [PubMed] [Google Scholar]
  41. Werner S., Weinberg W., Liao X., Peters K. G., Blessing M., Yuspa S. H., Weiner R. L., Williams L. T. Targeted expression of a dominant-negative FGF receptor mutant in the epidermis of transgenic mice reveals a role of FGF in keratinocyte organization and differentiation. EMBO J. 1993 Jul;12(7):2635–2643. doi: 10.1002/j.1460-2075.1993.tb05924.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Wientjes F. B., Segal A. W. NADPH oxidase and the respiratory burst. Semin Cell Biol. 1995 Dec;6(6):357–365. doi: 10.1016/s1043-4682(05)80006-6. [DOI] [PubMed] [Google Scholar]
  43. Wilkinson D. G., Bailes J. A., Champion J. E., McMahon A. P. A molecular analysis of mouse development from 8 to 10 days post coitum detects changes only in embryonic globin expression. Development. 1987 Apr;99(4):493–500. doi: 10.1242/dev.99.4.493. [DOI] [PubMed] [Google Scholar]
  44. Yet S. F., Perrella M. A., Layne M. D., Hsieh C. M., Maemura K., Kobzik L., Wiesel P., Christou H., Kourembanas S., Lee M. E. Hypoxia induces severe right ventricular dilatation and infarction in heme oxygenase-1 null mice. J Clin Invest. 1999 Apr;103(8):R23–R29. doi: 10.1172/JCI6163. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Yoshida T., Biro P., Cohen T., Müller R. M., Shibahara S. Human heme oxygenase cDNA and induction of its mRNA by hemin. Eur J Biochem. 1988 Feb 1;171(3):457–461. doi: 10.1111/j.1432-1033.1988.tb13811.x. [DOI] [PubMed] [Google Scholar]
  46. Ziegler D. M., Kehrer J. P. Oxygen radicals and drugs: in vitro measurements. Methods Enzymol. 1990;186:621–626. doi: 10.1016/0076-6879(90)86157-q. [DOI] [PubMed] [Google Scholar]

Articles from Biochemical Journal are provided here courtesy of The Biochemical Society

RESOURCES