u-0126 and Dermatitis--Contact

Ultraviolet B (UVB) radiation from the sun may lead to photocarcinogenesis of the skin. Sunscreens were used to protect the skin by reducing UVB irradiance, but sunscreen use did not reduce sunburn episodes. It was shown that UVB-induced erythema depends on surface exposure but not irradiance of UVB. We previously showed that irradiance plays a critical role in UVB-induced cell differentiation. This study investigated the impact of irradiance on UVB-induced photocarcinogenesis. For hairless mice receiving equivalent exposure of UVB radiation, the low irradiance (LI) UVB treated mice showed more rapid tumor development, larger tumor burden, and more keratinocytes harboring mutant p53 in the epidermis as compared to their high irradiance (HI) UVB treated counterpart. Mechanistically, using cell models, we demonstrated that LI UVB radiation allowed more keratinocytes harboring DNA damages to enter cell cycle via ERK-related signaling as compared to its HI UVB counterpart. These results indicated that at equivalent exposure, UVB radiation at LI has higher photocarcinogenic potential as compared to its HI counterpart. Since erythema is the observed sunburn at moderate doses and use of sunscreen was not found to associate with reduced sunburn episodes, the biological significance of sunburn with or without sunscreen use warrants further investigation.

Topics: Adult; Animals; Bromodeoxyuridine; Butadienes; Carcinogenesis; Cell Count; Cell Survival; Cells, Cultured; Dermatitis, Contact; DNA Damage; Extracellular Signal-Regulated MAP Kinases; G2 Phase; Humans; Immunosuppression Therapy; Keratinocytes; Mice, Hairless; Mitosis; Mutation; Nitriles; Protein Kinase Inhibitors; Pyrimidine Dimers; Skin Neoplasms; Tumor Suppressor Protein p53; Ultraviolet Rays

L-glutamine (Gln) is a nonessential amino acid that is the most abundant amino acid in plasma. Gln has been reported to have an anti-inflammatory activity that involves deactivation of mitogen-activated protein kinases (MAPKs) in a MAPK phosphatase (MKP)-1-dependent manner. This study investigated the role of Gln in the inhibition of DNFB-induced allergic contact dermatitis (CD) in the ears of mice, and specifically the involvement of Gln in p38 MAPK inhibition. Topical application of Gln or the p38 inhibitor, SB202190, suppressed DNFB-induced CD. Gln application inhibited DNFB-induced p38 phosphorylation. Western blot analysis revealed that Gln application resulted in early phosphorylation and protein induction of MKP-1. MKP-1 small interfering RNA (siRNA), but not control siRNA, abrogated Gln-mediated early phosphorylation, protein induction of MKP-1, deactivation of p38, and Gln-mediated suppression of CD. The extracellular signal-regulated kinase (ERK) inhibitor, U0126, blocked Gln-induced MKP-1 phosphorylation and protein induction, as well as Gln suppression of CD. These results suggest that Gln suppresses DNFB-induced CD via deactivation of p38 MAPK through the early induction of MKP-1, the negative regulator of p38, in an ERK-dependent manner.

Topics: Animals; Butadienes; Cell Line; Cells, Cultured; Dermatitis, Contact; Dinitrofluorobenzene; Disease Models, Animal; Dual Specificity Phosphatase 1; Enzyme Inhibitors; Female; Glutamine; Humans; Keratinocytes; MAP Kinase Kinase 4; Mice; Mice, Inbred C57BL; Nitriles; p38 Mitogen-Activated Protein Kinases; Phosphorylation; RNA, Small Interfering