Pine bark extract pycnogenol downregulates IFN-gamma-induced adhesion of T cells to human keratinocytes by inhibiting inducible ICAM-1 expression.
Expression of intercellular adhesion molecule-1 (ICAM-1) is necessary for leukocyte/keratinocyte interactions. Upregulation of ICAM-1 expression in keratinocytes has been observed in several inflammatory dermatoses, such as psoriasis, atopic dermatitis, and lupus erythematosus. Inflammatory cytokines, such as interferon-gamma (IFN-gamma), upregulate ICAM-1 expression in keratinocytes. Because of potent antioxidant and anti-inflammatory properties of the French maritime pine bark extract, Pycnogenol (Horphag Research, Geneva, Switzerland), its effects were investigated on the interaction of T cells with keratinocytes after activation with IFN-gamma and the molecular mechanisms involved in such interactions. Studies were performed using a human keratinocyte cell line, HaCaT. Cell adhesion in the presence of IFN-gamma was studied using a coculture assay. Treatment of HaCaT cells with 20 U/ml IFN-gamma for 24 h markedly induced adherence of Jurkat T cells to HaCaT cells. PYC pretreatment (50 microg/ml, 12 h) significantly inhibited IFN-gamma induced adherence of T cells to HaCaT cells (p < .01). ICAM-1 plays a major role in the IFN-gamma-induced adherence of T cells to keratinocytes. Thus, the effect of PYC on IFN-gamma-induced ICAM-1 expression was investigated as well. Pretreatment of HaCaT cells with PYC significantly inhibited IFN-gamma-induced expression of ICAM-1 expression in HaCaT cells. The downregulation of inducible ICAM-1 expression by PYC was both dose and time dependent. A 50 microg/ml dose of PYC and a 12 h pretreatment time (i.e., before activation with IFN-gamma) provided maximal (approximately 70%) inhibition of inducible ICAM-1 expression in HaCaT cells. Gamma-activated sequence present on the ICAM-1 gene confers IFN-gamma responsiveness in selected cells of epithelial origin (e.g., keratinocytes) that are known to express ICAM-1 on activation with IFN-gamma. Gel-shift assays revealed that PYC inhibits IFN-gamma-mediated activation of Stat1, thus suggesting a transcriptional regulation of inducible ICAM-1 expression by PYC. These results indicate the therapeutic potential of PYC in patients with inflammatory skin disorders.
Department of Molecular and Cell Biology, University of California, Berkeley 94720-3200, USA.
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D000975:Antioxidants / Q000494:pharmacology*; D002448:Cell Adhesion / Q000187:drug effects* / Q000502:physiology; D002460:Cell Line; D032462:Cycadopsida; D005419:Flavonoids / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics*; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D019169:Jurkat Cells; D015603:Keratinocytes / Q000502:physiology*; D015345:Oligonucleotide Probes; D010936:Plant Extracts; D012333:RNA, Messenger / Q000235:genetics; D013601:T-Lymphocytes / Q000187:drug effects / Q000502:physiology*; D014158:Transcription, Genetic / Q000187:drug effects*; D014197:Trees
D000975:Antioxidants; D005419:Flavonoids; D015345:Oligonucleotide Probes; D010936:Plant Extracts; D012333:RNA, Messenger; D018799:Intercellular Adhesion Molecule-1; C024070:pycnogenols; D007371:Interferon-gamma