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Abstract

UV irradiation elicits acute inflammation in the skin by increasing proinflammatory cytokine production in keratinocytes. However, the downstream protein target(s) that link UV radiation to the activation of signaling pathways responsible for cytokine expression have not been fully elucidated. In this study, we report a novel role of transglutaminase 2 (TG2), a member of the TG enzyme family whose activities are critical for cornified envelope formation, in mediating UV-induced inflammation. Our results showed that TG2-deficient mice exhibited reduced inflammatory responses to UV irradiation, including reduced erythema, edema, dilation of blood vessels, inflammatory cell infiltration, and levels of inflammatory cytokines. Using primary mouse keratinocytes and HaCaT cells, we found that UV irradiation-induced cytokine production by activating TG2, but not by upregulating TG2 expression, and that ER calcium release triggered by the UV-induced activation of phospholipase C was required for TG2 activation. Moreover, TG2 activity enhanced p65 phosphorylation, leading to an increase in NF-κB transcriptional activity. These results indicate that TG2 is a critical mediator of cytokine expression in the UV-induced inflammatory response of keratinocytes, and suggest that TG2 inhibition might be useful for preventing UV-related skin disorders, such as photoaging and skin cancer caused by chronic UV exposure. 

Author information

Lee SJ1, Lee KB1, Son YH1, Shin J1, Lee JH1, Kim HJ1, Hong AY1, Bae HW1, Kwon MA1, Lee WJ1, Kim JH2, Lee DH3,4, Jeong EM1,4, Kim IG1,4.

1Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, Seoul, Republic of Korea.2Department of Biomedical Laboratory Science, Cheongju University College of Health Science, Cheongju, Republic of Korea.3Department of Dermatology, Seoul National University College of Medicine, Seoul, Republic of Korea.4Institute of Human-Environment Interface Biology, Seoul National University College of Medicine, Seoul, Republic of Korea.