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

Matrix metalloproteinase (MMP)-9 expression induced by interleukin-1beta (IL-1beta) 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-kappaB) pathways participate in the induction of MMP-9 expression by IL-1beta. Zymographic, western blotting, and RT-PCR analyses showed that IL-1beta 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-1beta 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-kappaB inhibitor helenalin. Consistently, IL-1beta-stimulated translocation of NF-kappaB into the nucleus and degradation of inhibitory kappa B-alpha (IkappaB-alpha) 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-kappaB pathways is essential for IL-1beta-induced MMP-9 gene expression via transcription and translation processes. An increased understanding of the signal transduction pathways involved in IL-1beta-induced MMP-9 expression on RBA-1 may be of potential therapeutic value in the treatment of inflammatory disease.