4-phenylpyridine suppresses UVB-induced skin inflammation by targeting c-Src in vitro and in vivo

Acute or repetitive exposure to ultraviolet (UV) cause disruptions to the skin barrier and subsequent inflammatory skin disease. 4-phenylpyridine (4-PP) is a constituent of Brassica campestris L. ssp. Pekinensis and its effect on skin inflammation and molecular target remain unclear. The purpose of this study is to confirm the anti-inflammatory efficacy of 4-PP on UVB-induced skin inflammation in human keratinocytes HaCaT and mouse skin and validation of its molecular target. 4-PP also attenuated UVB-induced phosphorylation of p38/mitogen-activated protein kinase kinase (MKK) 3/6, c-Jun N-terminal kinase 1/2, MKK 4/7, extracellular-signal-regulated kinase 1/2, mitogen-activated protein kinase 1/2. Additionally, 4-PP inhibited UVB-induced phosphorylation of epidermal growth factor receptor (EGFR) Y1068, Y1045 and 854 residues but not the proto-oncogene tyrosine-protein kinase c-Src. Drug affinity responsive target stability assay revealed that 4-PP directly binds to c-Src and inhibits pronase c-proteolysis. Knockdown of c-Src inhibited UVB-induced COX-2 expression and phosphorylation of MAPKs and EGFR in HaCaT cells. Dorsal treatment of 4-PP prevented UVB (0.5 J/cm²)-induced skin thickness, phosphorylation of EGFR and COX-2 expression in mouse skin. Our findings suggest that 4-PP can be used as anti-inflammatory agent with an effect of skin inflammation by inhibiting the COX-2 expression via suppressing the c-Src/EGFR/MAPKs signalling pathway.