ABSTRACT
BACKGROUND: Tumour necrosis factor (TNF)-α inhibition is an effective treatment for moderate to severe plaque-type psoriasis. A change in the cytokine expression profile occurs in the skin after 4 days of treatment, preceding any clinical or histological improvements. MicroRNAs (miRNAs) are important post-transcriptional regulators of gene expression, but miRNA expression has never been studied in psoriatic skin during treatment. OBJECTIVE: To investigate changes in miRNA expression in psoriatic skin during adalimumab treatment and to compare results with changes in miRNA expression in a mouse model of Aldara-induced psoriasis-like skin inflammation. METHODS: Punch biopsies were obtained from nonlesional and lesional psoriatic skin during adalimumab treatment. In the mouse model of Aldara-induced skin inflammation, biopsies were obtained from TNF-α knockout (KO), IL-17A KO and wild-type mice. miRNA expression levels were analysed with microarray, reverse transcriptase quantitative polymerase chain reaction and in situ hybridization. RESULTS: In psoriatic skin, no changes in miRNA expression were seen 4 days after treatment initiation. After 14 days of treatment, the expression of several miRNAs was normalized towards the level seen in nonlesional skin before treatment. miR-23b expression increased after 14 days of treatment and remained high for 84 days, despite unaltered levels at baseline. In the mouse model of Aldara-induced skin inflammation, the level of miR-146a increased, whereas no regulation was seen for miR-203, miR-214-3p, miR-125a, miR-23b or let-7d-5p. CONCLUSIONS: This study demonstrates that the changes seen in the cytokine expression levels after 4 days of treatment with adalimumab are not facilitated by early changes in miRNA expression.
Subject(s)
Adalimumab/pharmacology , Anti-Inflammatory Agents/pharmacology , MicroRNAs/metabolism , Psoriasis/drug therapy , RNA, Messenger/metabolism , Adult , Aged , Aminoquinolines/toxicity , Animals , Case-Control Studies , Down-Regulation , Female , Humans , Imiquimod , Interleukin-8/metabolism , Irritants/toxicity , Male , Mice, Inbred C57BL , Mice, Knockout , MicroRNAs/drug effects , Middle Aged , RNA, Messenger/drug effectsABSTRACT
Naturally occurring hydrolyzable (HT) and condensed (CT) tannins and their monomeric units were tested for their ability to inhibit the stimulation of DNA synthesis by UVB radiation. Hairless mice were irradiated with either single (200 mJ/cm2) or multiple (150 mJ/cm2) doses of UVB applied at 24 h intervals and epidermal DNA synthesis was measured at different times after the last of these treatments. The peak of DNA synthesis that is observed 48-56 h after a single UVB irradiation shifts to an earlier time of 16-24 h after multiple UVB treatments. Interestingly, the early inhibitory period of DNA synthesis observed 8 h after a single UVB treatment is not detected following multiple UVB treatments. Rather, DNA synthesis is stimulated six-fold 24 h after multiple UVB treatment, a response that is higher than the peak occurring 48-56 h after a single UVB irradiation. The disappearance of the early period of inhibition when the peak of DNA synthesis shifts to an earlier time may be linked to reactive oxygen species brought to the epidermis by infiltrating leukocytes, which, in turn, act as second messengers to stimulate growth signals in cells. Topical applications of HT or CT remarkably inhibit the DNA responses to single and multiple UVB treatments, an effect that is dependent on the dose and time of administration. Indeed, the peak stimulation of DNA synthesis is maximally inhibited when 17 mg of Tarapod tannic acid (TA), an HT, are applied topically 20 min before a single UVB treatment. The polymeric tannins inhibited DNA synthesis to a greater degree than equal doses of their monomeric units, gallic acid and catechin. These results suggest that various oligomeric HT and CT may be useful against tumor-promoting responses associated with the exposure of skin to physical carcinogens.
Subject(s)
DNA Replication/radiation effects , DNA/radiation effects , Skin/radiation effects , Tannins/pharmacology , Ultraviolet Rays , Animals , DNA/biosynthesis , DNA/drug effects , DNA Replication/drug effects , Female , Kinetics , Male , Mice , Mice, Hairless , Plants , Skin/drug effects , Skin/metabolismABSTRACT
Naturally occurring hydrolyzable (HT) and condensed (CT) tannins and their monomeric units were tested for their ability to inhibit the induction of epidermal ODC activity and the formation of skin edema by UVB, two responses that are linked to the hyperplastic and inflammatory components of skin tumor promotion by this agent. Hairless mice were irradiated with either single (200 mJ/cm2/sec) or multiple (150 mJ/cm2/sec) doses of UVB and epidermal ODC activity was assayed at different times following irradiation. The peak of ODC induction which is observed 30-40 hours after a single UVB irradiation increases by 2.5 fold and shifts to a much earlier time of 5 hours after two UVB treatments repeated at 24-hour intervals. Topical applications of the various plant tannins, before or after irradiation, were found to inhibit, in a dose-dependent manner, epidermal ODC activity induced by single and multiple UVB treatments. Furthermore, the various HT and CT samples resulted in significant protection against UVB radiation-caused cutaneous edema. In general, the polymeric tannins inhibited ODC induction and edema to a greater degree than equal doses of their monomeric units, gallic acid and catechin. These results, in conjunction with our prior publications, suggest that various HTs and CTs may be useful against the hyperplastic and inflammatory responses associated with the exposure of skin to the tumor-promoting effects of both physical and chemical environmental carcinogens.
