Acrolein, an I-kappaBalpha-independent downregulator of NF-kappaB activity, causes the decrease in nitric oxide production in human malignant keratinocytes.

摘要

Acrolein, a reactive electrophilic alpha, beta-unsaturated aldehyde, is known to be an alkylating chemical carcinogen. The effect of acrolein on the activation of NF-kappaB in human malignant epidermal keratinocytes was examined to elucidate the molecular mechanism associated with this NF-kappaB-acrolein regulation and its consecutive sequence, nitric oxide (NO) production. Acrolein significantly downregulated the cellular NF-kappaB activity up to 60% compared with control as well as the lipopolysaccharide (LPS)-induced NO production in a dose response manner at concentrations of 10~30 muM. To investigate the regulatory mechanism associated with this NF-kappaB-acrolein downregulation, the relative level of phosphorylation of I-kappaBalpha (serines-32 and -36), a principle regulator of NF-kappaB activation, represented by acrolein, was quantified. Acrolein inhibited NF-kappaB activity without altering cellular levels of the phosphorylated and nonphosphorylated forms of I-kappaBalpha, implying that the downregulatory effect of acrolein on cellular NF-kappaB activity in human skin cells is an I-kappaBalpha-independent activation pathway. The results suggests that acrolein causes the decrease in nitric oxide production as an I-kappaBalpha-independent downregulator of NF-kappaB activity in human malignant keratinocytes, and acrolein-induced carcinogenesis may be associated with the modulation of cellular NF-kappaB activity.