CD40L induces matrix-metalloproteinase-9 but not tissue inhibitor of metalloproteinases-1 in cervical carcinoma cells: Imbalance between NF-kappa B and STAT3 activation

Matrix-metalloproteinases (MMPs) are essentially required for tumor cell in vasion and metastasis. Production of precursor enzymes is regulated on tran scriptional level, while activation of the pro-enzymes is tightly controlle d by posttranscriptional mechanisms. The enzyme activity can be blocked by specific tissue inhibitors of MMPs (TIMPs). In cervical carcinomas strong u p-regulation of the type IV collagenase MMP-9 had been demonstrated. We sho w that activation of CD40, a receptor highly expressed on cervical carcinom as, induces MMP-9 in cervical carcinoma cells, whereas TIMP-1 production in hibiting MMP-9 activity was not affected. This gene induction pattern corre sponded to the differential activation of the transcription factor nuclear factor kappaB (NF-kappaB) regulating MMP-9, but not signal transducer and a ctivator of transcription 3 (STAT3), which is involved in TIMP-1 gene regul ation. Transient expression of the CD40-inducible NF-kappaB subunit p65 was sufficient for MMP-9 induction. Agents that suppressed CD40-mediated NF-ka ppaB activation also reduced MMP-9 induction, further supporting an importa nt role of NF-kappaB in CD40-mediated MMP-9 induction, Our data suggest tha t CD40 expression in carcinoma cells might convert a CD40L-dependent immuno logical defense signal into a tumor-promoting signal. Selective CD40-mediat ed signaling through NF-kappaB but not STAT3 correlates to a shift of the b alance between MMP-9 and TIMP-1 toward the protease, (C) 2001 Academic Pres s.