Langerhans cells, keratinocytes, nitric oxide and psoriasis

Abstract

In a comprehensive and thought-provoking article in Immunology Today[1xMorhenn, V.B. Immunol. Today. 1997; 18: 433–436Abstract | Full Text PDF | PubMed | Scopus (48)See all References[1], V.B. Morhenn proposed a role for nitric oxide (NO) and Langerhans cells (LCs) in the triggering of psoriasis. However, our studies suggest that NO release is a secondary event following trauma-induced cytokine release from the much more numerous keratinocytes (KCs).Decreased protein kinase II β (PKCIIβ) levels in psoriatic epidermis indicate that the LCs have been activated, but does not show whether they were activated first. The psoriasiform changes in epidermis induced by PKC activation can be produced equally well by overexpression of interleukin 1 receptor I (IL-1RI) in transgenic mice[2xGroves, R.W., Rauschmayr, T., Nakamura, K., Sarkar, S., Williams, I.R., and Kupper, T.S. J. Clin. Invest. 1996; 98: 336–344Crossref | PubMedSee all References[2]or by irritants such as acetone. Moreover, in the majority of cell types, cytokines are necessary for inducible nitric oxide synthase (iNOS) production, rather than the induction of cytokines by NO.Immunostaining of iNOS in psoriatic lesions shows it to be associated with KCs (Refs [3xKolb-Bachofen, V., Fehsel, K., Michel, G., and Ruzicka, T. Lancet. 1994; 344: 139Abstract | PubMed | Scopus (66)See all References, 4xBruch-Gerharz, D., Fehsel, K., Suschek, C., Michel, G., Ruzicka, T., and Kolb-Bachofen, V. J. Exp. Med. 1996; 184: 2007–2012Crossref | PubMedSee all References]). Over psoriatic plaques, we recorded levels of NO 18-fold higher than over non-lesional skin and 200-fold higher than over normal skin[5xWeller, R. and Ormerod, A. Br. J. Dermatol. 1997; 136: 136–137Crossref | PubMedSee all References[5]: it is hard to imagine that all this NO is produced by the LCs. In vitro incubation of KCs with IL-1β and tumour necrosis factor α (TNF-α), induces iNOS mRNA production[6xSirsjo, S., Karlsson, M., Gidloef, A., and Toermae, H. Br. J. Dermatol. 1996; 134: 643–648Crossref | PubMedSee all References[6]. Both IL-1β and TNF-α are pre-formed in KCs (Ref. [7xOxholm, A., Oxholm, P., Staberg, B., and Bendtzen, K. Br. J. Dermatol. 1988; 118: 369–376Crossref | PubMedSee all References[7]), can be released following UVB or trauma, and are expressed at high levels in psoriatic epidermis together with IL-8 (reviewed in Refs [4xBruch-Gerharz, D., Fehsel, K., Suschek, C., Michel, G., Ruzicka, T., and Kolb-Bachofen, V. J. Exp. Med. 1996; 184: 2007–2012Crossref | PubMedSee all References, 8xWeller, R. Br. J. Dermatol. 1997; 137: 665–672Crossref | PubMedSee all References]). The effects of these cytokines on adhesion molecules and leukocyte chemotaxis would promote skin infiltration. KCs can also be stimulated to produce NO by several physiological stimuli, including UVB (reviewed in Ref. [8xWeller, R. Br. J. Dermatol. 1997; 137: 665–672Crossref | PubMedSee all References[8]).The effects of cyclic GMP (cGMP) on KCs are controversial: some studies suggest that it arrests KC proliferation and promotes differentiation[9xWilkinson, D.I., Liu, S.C., and Orenberg, E.K. J. Invest. Dermatol. 1981; 71: 385–388CrossrefSee all References[9], possibly by cGMP-gated Ca2+ channel activation[10xOda, Y., Timpe, L.C., McKenzie, R.C., Sauder, D.N., Largman, C., and Mauro, T. FEBS Lett. 1997; 414: 140–145Abstract | Full Text | Full Text PDF | PubMed | Scopus (17)See all References[10]. Treatment of normal KCs with interferon γ (IFN-γ) induces iNOS and inhibits normal KC growth[11xArany, I., Brysk, M.M., Brysk, H., and Tyring, S.K. Biochem. Biophys. Res. Commun. 1996; 210: 618–622Crossref | Scopus (64)See all References, 12xHeck, D.E., Laskin, D.L., Gardner, C.R., and Laskin, J.D. J. Biol. Chem. 1992; 267: 21277–21280PubMedSee all References]. From the high NO levels we measured[5xWeller, R. and Ormerod, A. Br. J. Dermatol. 1997; 136: 136–137Crossref | PubMedSee all References[5], it is clear that psoriatic KCs do produce ample NO, which should overcome growth stimulation by epidermal growth factor[12xHeck, D.E., Laskin, D.L., Gardner, C.R., and Laskin, J.D. J. Biol. Chem. 1992; 267: 21277–21280PubMedSee all References[12]. High doses of NO also inhibit the growth of T helper 1 (Th1) cells (reviewed in Ref. [8xWeller, R. Br. J. Dermatol. 1997; 137: 665–672Crossref | PubMedSee all References[8]). That psoriatic KC growth and T-cell activation continue despite high levels of NO and intracellular cGMP suggests a fundamental defect in the KC response to NO (or IFN-γ), which should be investigated. The question is whether NO production stimulates inflammation, or whether NO release is a secondary event caused by cytokine induction of iNOS and represents an attempt by the skin to restore homeostasis.Note added in proof: recently we have found that KCs from non-lesional psoriatic skin produce twice as much NO as produced by normal adult KCs.