Effects of cyclosporine on cytokines and cytokine receptors inpsoriasis

Abstract

We read with interest the article by Prens et al. on the effects of cyclosporine on cytokines and cytokine receptors in psoriasis (J Am Acad Dermatol 1995;33:947-53). The authors, using immunohistochemical stains, demonstrated that both interleukin-1β (IL-1β) and IL-8 are significantly reduced in keratinocytes after treatment with cyclosporine. They state that inhibition of IL-1β is probably important in the alleviation of psoriasis because this is an early cytokine in the cytokine cascade and theoretically is considered to be able to induce most other cytokines. Although we are aware that IL-1β is increased at the protein and messenger RNA levels within psoriasis, we are not aware of any definitive studies that have demonstrated an increase in functional IL-1β produced by keratinocytes in psoriasis. 1Prens EP Benne K van Damme J et al.Interleukin-1 and interleukin-6 in psoriasis.J Invest Dermatol. 1990; 95: 121S-124SAbstract Full Text PDF PubMed Google Scholar, 2Uyemura K Yamamura M Fivenson DF et al.The cyto kine network in lesional and lesion-free psoriasis skin is characterized by a T-helper type 1 cell-mediated response.J Invest Dermatol. 1993; 101: 701-705Abstract Full Text PDF PubMed Google Scholar, 3Debets R van Joost Th Benner R et al.Psoriatic epidermal cells release elevated levels of immunoreactive and biologically active interleukin 1 and 6: modulation by corticosteroid treatment.in: Molecular biology to therapeutics: pharmacology and the skin. vol 5. Karger, Basel1993: 158-166Google Scholar, 4Cooper KD Hammerberg C Baadsgaard O et al.IL-1 activity is reduced in psoriatic skin: decreased IL-1 alpha and increased nonfunctional IL-1 beta.J Immunol. 1990; 144: 4593-4603PubMed Google Scholar, 5Gearing AJH Fincham NJ Bird CR et al.Cytokines in skin of psoriasis.Cytokine. 1990; 2: 68-75Crossref PubMed Scopus (119) Google Scholar Even in the chapter by Debets et al., 3Debets R van Joost Th Benner R et al.Psoriatic epidermal cells release elevated levels of immunoreactive and biologically active interleukin 1 and 6: modulation by corticosteroid treatment.in: Molecular biology to therapeutics: pharmacology and the skin. vol 5. Karger, Basel1993: 158-166Google Scholar a dermal origin for the functional IL-1β in psoriatic skin could not be eliminated, and these authors commented that other investigators 4Cooper KD Hammerberg C Baadsgaard O et al.IL-1 activity is reduced in psoriatic skin: decreased IL-1 alpha and increased nonfunctional IL-1 beta.J Immunol. 1990; 144: 4593-4603PubMed Google Scholar, 5Gearing AJH Fincham NJ Bird CR et al.Cytokines in skin of psoriasis.Cytokine. 1990; 2: 68-75Crossref PubMed Scopus (119) Google Scholar have not demonstrated increased functional IL-1β of epidermal origin in psoriasis. For cells to produce functional IL-1β, they must also produce a functional cysteine protease designated IL-1β-converting enzyme (ICE), which converts the inactive form of IL-1β to the active form at the cell membrane. This enzyme is not present in normal keratinocytes, and functional ICE has not been demonstrated in epidermal keratinocytes except in rare instances. 6Zepter K Haeffner AC Chavinson J et al.Keratinocyte-derived mature IL-1beta induction of the IL-1beta converting enzyme (ICE) by keratinocytes.J Invest Dermatol. 1995; 104 ([abstract]): 587Crossref Scopus (12) Google Scholar If functional ICE is present within epidermal keratinocytes in psoriasis and functional IL-1β is produced, this may suggest a new class of effective topical therapeutic agents for psoriasis. ICE is a novel protease for which there are specific protease inhibitors already known and others under development. 7Thornberry NA Molineaux SM. Interleukin-1beta converting enzyme: a novel cysteine protease required for IL-1beta production and implicated in programmed cell death.Protein Sci. 1995; 4: 3-12Crossref PubMed Scopus (151) Google Scholar, 8Ray CA Black RA Kronheim SR et al.Viral inhibition of inflammation: cowpox virus encodes an inhibitor of the interleukin-1beta converting enzyme.Cell. 1992; 69: 597-604Abstract Full Text PDF PubMed Scopus (886) Google Scholar, 9Dolle RE Singh J Rinker J et al.Aspartyl alpha-((1-Phenyl-3-(trifluoromethyl)-pyrazol-5-yl)oxy)methyl ketones as interleukin-1beta converting enzyme inhibitors: significance of the P1 and P3 amido nitrogens for enzyme-peptide inhibitor binding.J Med Chem. 1994; 37: 3663-3666Crossref PubMed Scopus (58) Google Scholar