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Human skin is ubiquitously exposed to UV radiation (UVR). These data suggest that interference with the TLR4/MyD88 pathway may be a useful tool in promoting DNA repair and maintaining immune responses following UVR-induced damage. Lymphoblasts deficient in DNA repair (derived from a xeroderma pigmentosum group A patient) failed to augment DNA repair after MyD88 knockdown after UVR, in contrast to lymphoblasts from a healthy control. Both in vitro treatment of MyD88 −/− APCs with and intradermal in vivo injections of PARP inhibitor, PJ-34, caused WT-level cyclobutane pyrimidine dimer repair.
Epidermal DNA from in vivo UV-irradiated MyD88 −/− mice had an increased resolution rate of cyclobutane pyrimidine dimers. Cultured, UV-irradiated WT APCs showed cleavage (inactivation) of the DNA damage–recognition molecule PARP, whereas PARP persisted in MyD88 −/− and TLR4 −/− APCs. Even with normal UV-induced, dendritic cell migration, DNA damage in the local lymph nodes was less pronounced in MyD88 −/− mice compared with WT mice. In the dinitrofluorobenzene contact hypersensitivity model, UV-irradiated MyD88-deficient (MyD88 −/−) C57BL/6 mice had intact ear swelling, exaggerated inflammation, and higher levels of dinitrofluorobenzene-specific IgG2a compared with wild-type (WT) mice.
We reported previously that the TLR4–MyD88 signaling axis is necessary for UV-induced apoptosis. UV radiation (UVR) induces DNA damage, leading to the accumulation of mutations in epidermal keratinocytes and immunosuppression, which contribute to the development of nonmelanoma skin cancer.
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