Cyclosporin A rapidly inhibits epidermal cytokine expression in psoriasis lesions, but not in cytokine-stimulated cultured keratinocytes.
To better understand the cellular target(s) of cyclosporin action in psoriasis, we have studied the effects of systemic short-term (7 d), low-dose (3-7.5 mg/kg) cyclosporin A administration on the expression of the cytokines interleukin (IL)-8 and IL-1 beta in psoriatic lesions. RNA blot hybridization analysis of pretreatment keratome biopsies revealed that expression of both cytokine mRNAs was highly variable from patient to patient. Significant covariation of both cytokine mRNA levels was noted (r = 0.86, p < 0.0001). However, there was no significant correlation between expression of either cytokine and clinical severity, as measured by the pretreatment Psoriasis Area and Severity Index (PASI). IL-1 beta protein levels measured by enzyme-linked immunosorbent assay (ELISA) were highly correlated with IL-1 beta mRNA levels, indicating that the differences in transcript levels accurately reflect differences in epidermal cytokine protein. Significant reductions in both cytokine transcripts and in IL-1 beta immunoreactive protein were noted in the high expression subgroup after 1 week of cyclosporin A therapy, prior to detectable clinical improvement. In contrast to its pronounced effects on epidermal cytokine expression in vivo and the allogeneic mixed lymphocyte reaction in vitro, cyclosporine A did not inhibit the induction of intercellular adhesion molecule (ICAM)-1 or IL-8 mRNAs by cultured keratinocytes in response to IL-1 beta or the combination of tumor necrosis factor (TNF)-alpha and interferon (IFN)-gamma. These data suggest that epidermal keratinocytes respond to signals produced by activated T cells by coordinate expression of multiple cytokines, and that cyclosporin A acts primarily through blockade of T cells, rather than through keratinocyte activation.
Elder
J T
JT
Department of Dermatology, University of Michigan, Ann Arbor.
Hammerberg
C
C
Cooper
K D
KD
Kojima
T
T
Nair
R P
RP
Ellis
C N
CN
Voorhees
J J
JJ
D015152:Blotting, Northern; D002478:Cells, Cultured; D016572:Cyclosporine / Q000494:pharmacology*; D016207:Cytokines / Q000235:genetics / Q000502:physiology*; D004797:Enzyme-Linked Immunosorbent Assay; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007375:Interleukin-1 / Q000235:genetics; D015603:Keratinocytes / Q000187:drug effects*; D011565:Psoriasis / Q000188:drug therapy / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis; D012867:Skin / Q000737:chemistry*; D014222:Triamcinolone Acetonide / Q000494:pharmacology
D016207:Cytokines; D007375:Interleukin-1; D012333:RNA, Messenger; D016572:Cyclosporine; D014222:Triamcinolone Acetonide