In addition to their antibiotic effects, tetracyclines have anti-inflammatory action that is often beneficial in the control of inflammatory skin disorders. In this study, we examined the effects of tetracycline (TET) and two of its derivatives, doxycycline (DOX) and minocycline (MIN), on the production of interleukin-8 (IL-8) elicited by the activation of protease-activated receptor 2 (PAR2) in normal human epidermal keratinocytes (NHEK). In NHEK, the production of IL-8 stimulated by an agonist peptide of PAR2, SLIGKIV-NH 2 , at 100 M was significantly reduced by TET, DOX, or MIN at 5 and 10 M, concentrations that are noncytotoxic. The tumor necrosis factor alpha (TNF-␣)-induced production of IL-8 was synergistically augmented by SLIGKIV-NH 2 , and that synergistic increase in the production of IL-8 was suppressed by 100 nM PAR2-specific small interfering RNA. It was also suppressed by TET, DOX, or MIN but not by the 14-membered-ring macrolide antibiotics erythromycin, roxithromycin, and clarithromycin, which also have anti-inflammatory activities, at 10 M. These results suggest that tetracyclines attenuate the PAR2-IL-8 axis in keratinocytes and thereby effectively modulate proinflammatory responses in the skin.

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As previous reports have shown, we present that the neonates with central venous catheterization were more likely to be infected with MRSA. We also need to pay attention to neonates with digestive system diseases, showing signs of infection, because they may be potentially infected with MRSA.

The production of interleukin-8 induced by the activation of protease-activated receptor 2 and its synergism with interleukin-1␤ were modulated by 14-membered-ring macrolides, namely, roxithromycin, erythromycin, and clarithromycin, in cultured normal human epidermal keratinocytes. Those macrolides may attenuate the protease-activated receptor 2-interleukin-8 axis and thereby modulate proinflammatory responses in the skin.

A novel point mutation of keratin 17 (KRT17) in a Japanese family with pachyonychia congenita type 2: an RNA-based genetic analysis using a single hair bulb

Adenosine causes the anti-inflammatory effect of MTX; however, the contributions of synoviocyte adenosine receptors (AdoRs) are unknown, and matrix metalloproteinase 3 (MMP-3) is released by fibroblast-like synoviocytes in response to inflammatory signaling. To understand the mechanism of the clinical observation that the matrix proteinase-3 concentration of patients with rheumatoid arthritis treated successfully with methotrexate does not usually normalize, we investigated the effects of A2A AdoR activation and inhibition on tumor necrosis factor-alpha (TNFα)-induced MMP-3 release by MH7A human rheumatoid synovial cells. MH7A cells constitutively expressed membrane-associated A2A AdoRs, and HENECA enhanced intracellular cAMP. Stimulation with TNFα markedly enhanced release of MMP-3 from MH7A cells, whereas HENECA partially and dose-dependently inhibited TNFα-evoked MMP-3 release. Similarly, dbcAMP partially inhibited TNFα-induced MMP-3 release. Pretreatment with ZM241385 reversed the inhibitory effects of HENECA. Further, TNFα induced p38 MAPK and ATF-2 phosphorylation, whereas HENECA suppressed p38 MAPK and ATF-2 phosphorylation. We concluded that adenosine signaling via A2A AdoRs, adenylyl cyclase, and cAMP reduces TNFα-induced MMP-3 production by interfering with p38 MAPK/ATF-2 activity. Activation of A2A AdoR signaling alone using HENECA did not reduce TNFα-induced MMP-3 production to the basal levels, which may explain why MTX usually decreases but does not eliminate serum MMP-3.

BackgroundAdenosine is the effector molecule mediating the antirheumatic effects of methotrexate, but the contributions of synoviocyte adenosine receptors (AdoRs) are unknown. Matrix metalloproteinase 3 (MMP-3) is released by fibroblast-like synoviocytes in response to inflammatory signaling, and serum MMP-3 is elevated during active rheumatoid arthritis. To elucidate the therapeutic mechanisms of methotrexate, we investigated the effects of A2A AdoR activation and inhibition on tumor necrosis factor-alpha (TNFa)-induced MMP-3 release by MH7A human rheumatoid synovial cells.MethodsCultured MH7A cells were treated with 25 pg/ml TNFa or vehicle for 24 h in the presence or absence of the selective A2A AdoR agonist HENECA (10, 50, or 100 nM), and MMP-3 release was measured in the culture supernatant. In other experiments, cells were treated with TNFa plus the cAMP analog dbcAMP or pretreated with the A2A AdoR antagonist ZM241385 prior to TNFa with or without HENECA. Activation of the p38 MAPK signaling pathway was evaluated by western blotting of phosphorylated signaling proteins. Treatment group means were compared by independent samples t-tests.ResultsMH7A cells constitutively expressed membrane-associated A2A AdoRs, and HENECA enhanced intracellular cAMP, indicating that these receptors are functionally coupled to adenylyl cyclase. Stimulation with TNFa markedly enhanced release of MMP-3 from MH7A cells, whereas HENECA partially and dose-dependently inhibited TNFa-evoked MMP-3 release. Similarly, dbcAMP partially inhibited TNFa-induced MMP-3 release. Pretreatment with ZM241385 reversed the inhibitory effects of HENECA. Further, TNFa induced p38 MAPK and ATF-2 phosphorylation, whereas HENECA suppressed p38 MAPK and ATF-2 phosphorylation.ConclusionsAdenosine signaling via A2A AdoRs, adenylyl cyclase, and cAMP reduces (although does not completely block) TNFa-induced MMP-3 production, by interfering with p38 MAPK/ATF-2 activity. Activation of A2A AdoR pathway and suppression of MMP-3 release may explain the antirheumatic effects of methotrexate.