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.