Involvement of p42/p44 MAPK, p38 MAPK, JNK and nuclear factor‐kappa B in interleukin‐1β‐induced matrix metalloproteinase‐9 expression in rat brain astrocytes

Abstract Matrix metalloproteinase (MMP)‐9 expression induced by interleukin‐1β (IL‐1β) was investigated in rat brain astrocyte‐1 (RBA‐1). Here we report that the mitogen‐activated protein kinases (MAPKs) and nuclear factor‐kappa B (NF‐κB) pathways participate in the induction of MMP‐9 expression by IL‐1β. Zymographic, western blotting, and RT‐PCR analyses showed that IL‐1β increased expression of MMP‐9 mRNA and protein, which were inhibited by inhibitors of MEK1/2 (U0126), p38 (SB202190), and JNK (SP600125). In accordance with these findings, IL‐1β stimulated phosphorylation of p42/p44 MAPK, p38, and c‐Jun N‐terminal kinase (JNK), which was attenuated by U0126, SB202190, or SP600125, respectively. Furthermore, this up‐regulation of MMP‐9 mRNA and protein was blocked by a specific NF‐κB inhibitor helenalin. Consistently, IL‐1β‐stimulated translocation of NF‐κB into the nucleus and degradation of inhibitory kappa B‐α (IκB‐α) was revealed by western blotting and immunofluorescence staining, which was blocked by helenalin, but not by U0126, SB202190, or SP600125. Taken together, these results suggest that in RBA‐1 cells, activation of p42/p44 MAPK, p38, JNK and NF‐κB pathways is essential for IL‐1β‐induced MMP‐9 gene expression via transcription and translation processes. An increased understanding of the signal transduction pathways involved in IL‐1β‐induced MMP‐9 expression on RBA‐1 may be of potential therapeutic value in the treatment of inflammatory disease.