This paper is only available as a PDF. To read, Please Download here.
Abstract
The present study was conducted to determine whether cyclosporin A (CsA) and FK506
could be effective in inhibiting the proliferation and cytokine secretion of normal
human epidermal keratinocytes (NHEK). NHEK proliferation in the presence of CsA and
FK506 at the concentrations 10−9 to 10−5 M at 24 and 48 h time points was measured colorimetrically by the MTS assay. CsA
had inhibitory effects from 10−6 to 10−5 M, while FK506 had no effect, except for toxicity at the very highest concentrations
(5 × 10−6 M and higher). NHEK cells spontaneously secrete IL-8 (243.4 ± 55.5 pg/ml), and this
baseline level was augmented by TNF-α alone, or synergistically by TNF-α and IFN-γ,
which are thought to be secreted by T cells. Neither CsA nor FK506 had any significant
effect on either spontaneous or cytokine-stimulated keratinocyte IL-8 production.
Therefore, it is most likely that the two drugs indirectly inhibit the keratinocyte
inflammatory response through their actions on T cells or other immunocompetent cells.
Keywords
Abbreviations:
MTS ((3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethophenyl)-2-(4-sulfophenyl)-2H-tetrazolium) or Owen's reagent), PMS (phenazine methosulfate)To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Journal of Dermatological ScienceAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Cyclosporine: a new immunosuppressive agent for organ transplantation.Ann Int Med. 1984; 101: 667-682
- Low-dose cyclosporin versus placebo in patients with rheumatoid arthritis.Lancet. 1990; 335: 1051-1055
- Cyclosporine improves psoriasis in a double-blind study.J Am Med Assoc. 1986; 256: 3110-3116
- Cyclosporine for plaque-type psoriasis. Results of a multidose, double- blind trial.N Engl J Med. 1991; 324: 277-284
- FK506 for liver, kidney, and pancreas transplantation.Lancet. 1989; ii: 1000-1004
- Suppression of autoimmune thyroid disease by FK 506: influence on thyroid infiltrating cells, adhesion molecule expression and anti-thyroglobulin antibody production.Clin Exp Immunol. 1993; 91: 368-375
- Tacrolimus (FK506)—a new therapeutic agent for severe recalcitrant psoriasis.Arch Dermatol. 1992; 128: 781-785
- FK506, a novel immunosuppressant isolated from a streptomyces II. Immunosuppressive effect of FK-506 in vitro.J Antibiot. 1987; 40: 1256-1265
- Novel immunosuppressive agent, FK506. In vitro effects on the cloned T cell activation.J Immunol. 1987; 139: 1797-1803
- Cyclosporin A and FK506 mediate differential effects on T cell activation in vivo.J Immunol. 1992; 148: 1049-1054
- Cyclosporine A and FK506 show similar immunosuppressive effects on long-term in vitro T-cell proliferation.Int J Immunopharm. 1993; 15: 93-97
- The mechanism of action of cyclosporin A and FK506.Immunol Today. 1992; 13: 136-142
- Chemistry and biology of the immunophilins and their immunosuppressive ligands (Review).Science. 1991; 251: 283-287
- FK-506 and cyclosporin A: immunosuppressive mechanism of action and beyond.Curr Opin Immunol. 1992; 4: 548-552
- Calcineurin is a common target of cyclophilin-cyclosporin A and FKBP-FK506 complexes.Cell. 1991; 66: 807-815
- Identification of calcineurin as a key signaling enzyme in T-lymphocyte activation.Nature. 1992; 357: 695-697
- NF- ATp, a T lymphocyte DNA-binding protein that is a target for calcineurin and immunosuppressive drugs.J Biol Chem. 1993; 268: 3747-3752
- Anti-inflammatory effect of FK-506 on human skin mast cells.J Invest Dermatol. 1992; 99: 723-728
- Rapamycin and FK506 differentially inhibit mast cell cytokine production and cytokine-induced proliferation and act as reciprocal antagonists.J Pharm Exp Therap. 1992; 261: 970-976
- Cyclosporin A inhibits the antigen-presenting functions of freshly isolated human Langerhans cells in vitro.J Invest Dermatol. 1991; 96: 408-413
- The activated keratinocyte: a model for inducible cytokine production by non-bone marrow-derived cells in cutaneous inflammatory and immune responses.J Invest Dermatol. 1990; 94: 146-150
- Cytokine expression by epidermal cell subpopulations.J Invest Dermatol. 1992; 99: 42-45
- Differential induction of intercellular adhesion molecule-1 in human skin by recombinant cytokines.J Cutan Pathol. 1993; 20: 21-27
- Superantigenic staphylococcal exotoxins induce T-cell proliferation in the presence of Langerhans cells or class II-bearing keratinocytes and stimulate keratinocytes to produce T- cell-activating cytokines.J Invest Dermatol. 1994; 102: 31-38
- Interferon gammatreated keratinocytes activate T cells in the presence of superantigens: involvement of major histocompatibility complex class II molecules.J Invest Dermatol. 1994; 102: 150-154
- Detection of the FK506-FKBP-calcineurin complex by a simple binding assay.Biochem Biophys Res Commun. 1993; 192: 1388-1394
- Upper keratinocytes of psoriatic skin lesions express high levels ofJ Invest Dermatol. 1991; 97: 73-79
![Math Eq]()
mRNA in situ. - Cellular localization of interleukin-8 and its inducer, tumor necrosis factor-alpha in psoriasis.Am J Pathol. 1991; 138: 129-140
- Modulation of keratinocyte-derived interleukin-8 which is chemotactic for neutrophils and T lymphocytes.Am J Pathol. 1991; 139: 869-876
- Interleukin-8 stimulates calcium transients and promotes epidermal cell proliferation.J Invest Dermatol. 1992; 99: 294-298
- Production of interleukin-8 by human dermal fibroblasts and keratinocytes in response to interleukin-1 or tumour necrosis factor.Immunology. 1989; 68: 31-36
- Marked synergism between tumor necrosis factor-α and interferon-γ in regulation of keratinocyte derived adhesion molecules and chemotactic factors.J Clin Invest. 1990; 85: 605-608
- Increased expression of epidermal IL-8 receptor in psoriasis. Down-regulation by FK-506 in vitro.J Immunol. 1993; 151: 4399-4406
- The effect of cyclosporin A on epidermal cells II. Cyclosporin A inhibits proliferation of normal and transformed keratinocytes.J Invest Dermatol. 1988; 90: 796-800
- Effects of cyclosporin A on cultured human epidermal keratinocytes. Growth and 5-bromo-2′-deoxyuridine incorporation.Acta Derm Venereol. 1990; 70: 6-10
- The effect of cyclosporin on human epidermal keratinocytes in vitro.Br J Dermatol. 1990; 122: 173-180
- Time-dependent inhibition of growth of human keratinocytes and fibroblasts by cyclosporin A: effect on keratinocytes at therapeutic blood levels.Br J Dermatol. 1990; 123: 207-213
- Cyclosporin A inhibits directly in vivo keratinocyte proliferation of living human skin.J Invest Dermatol. 1989; 92: 755-757
- Cydosporin A exerts a cytostatic effect in vivo on human and murine epithelial cells.Cancer. 1990; 66: 936-940
- Effects of cyclosporin A on resident and passenger immune cells of normal human skin and UV-induced erythema reactions.Br J Dermatol. 1992; 127: 560-565
- Use of an aqueous soluble tetrazolium/formazan assay to measure viability and proliferation of tymphokine dependent cell lines.J Immunol Methods. 1993; 157: 233-240
- Folate receptor allows cells to grow in low concentrations of 5-methyltetrahydrofolate.in: 3rd ed. Proc Natl Acad Sci USA. 89. 1992: 6006-6009
- IL-8 gene expression and production in human keratinocytes and their modulation by UVB.J Invest Dermatol. 1993; 101: 690-694
- The mechanisms of action of cyclosporin A in the treatment of psoriasis.Immunol Today. 1993; 14: 69-74
- Cyclosporin A rapidly inhibits epidermal cytokine expression in psoriasis lesions, but not cytokine-stimulated cultured keratinocytes.J Invest Dermatol. 1993; 101: 761-766
- GRO-α mRNA is selectively overexpressed in psoriatic epidermis and is reduced by cyclosporin A in vivo, but not in cultured keratinocytes.J Invest Dermatol. 1993; 101: 767-772
- Identification of a putative regulator of early T cell activation genes.Science. 1988; 241: 202-205
- Distinct mechanisms for regulation of the interleukin-8 gene involve synergism and cooperativity betweenMol Cell Biol. 1993; 13: 7191-7198
![Math Eq]()
and NF-κB. - FK506 inhibits cytokine gene and adhesion molecule expression in psoriatic skin lesions.Ann NY Acad Sci. 1993; 696: 250-256
mRNA in situ.
and NF-κB.Article info
Publication history
Accepted:
December 21,
1994
Received in revised form:
December 5,
1994
Received:
July 6,
1994
Identification
Copyright
© 1995 Published by Elsevier Inc.
