All-trans-retinoic acid induces interleukin-8 via the nuclear factor-kappaB and p38 mitogen-activated protein kinase pathways in normal human keratinocytes.
Retinoic acid derivatives have been used successfully for the treatment of various dermatoses, such as psoriasis; however, topical application of these compounds often elicits skin irritation. We hypothesized that this irritation was as a result of the local production of interleukin-8 (IL-8). To test this hypothesis, we investigated whether all-trans-retinoic acid (ATRA) induced IL-8 production in normal human keratinocytes. Stimulation with 10(-7) M ATRA enhanced IL-8 mRNA expression and induced IL-8 production. We also studied the intracellular signaling mechanisms of ATRA-induced IL-8 production in keratinocytes. ATRA increased the expression of RelA (p65), RelB, nuclear factor (NF)-kappaB2 (p52), and NF-kappaB1 (p50), and elevated the DNA-binding activity of p65 and phosphorylation of inhibitor kappaB (IkappaB) alpha. Introduction of a dominant-negative mutant of IkappaBalpha completely abolished ATRA-induced IL-8 production, which indicates that this process is NF-kappaB-dependent. We also studied the role of the p38 mitogen-activated protein kinase (MAPK) pathway in this phenomenon. ATRA phosphorylated the p38 MAPK, and SB202180 inhibited ATRA-induced IL-8 production, which indicates that the p38 MAPK is also involved in ATRA-induced IL-8 production. In summary, ATRA induces IL-8 production in both NF-kappaB- and p38 MAPK-dependent manners in normal human keratinocytes.
Dai
Xiuju
X
Department of Dermatology, Ehime University School of Medicine, Ehime, Japan.
Yamasaki
Kenshi
K
Shirakata
Yuji
Y
Sayama
Koji
K
Hashimoto
Koji
K
D000970:Antineoplastic Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D020672:I-kappa B Proteins / Q000235:genetics / Q000378:metabolism; D016209:Interleukin-8 / Q000235:genetics*; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D016296:Mutagenesis; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D051996:Transcription Factor RelA; D014212:Tretinoin / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D020672:I-kappa B Proteins; D016209:Interleukin-8; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D051996:Transcription Factor RelA; D000072000:NF-KappaB Inhibitor alpha; D014212:Tretinoin; D048051:p38 Mitogen-Activated Protein Kinases