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Published online before print February 8, 2007

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(Journal of Leukocyte Biology. 2007;81:1303-1310.)
© 2007 by Society for Leukocyte Biology

Relaxin-induced matrix metalloproteinase-9 expression is associated with activation of the NF-B pathway in human THP-1 cells

Department of Animal Sciences, Rutgers University, New Brunswick, New Jersey, USA

² Correspondence: Department of Animal Sciences, Rutgers University, New Brunswick, NJ 08901-8525, USA. E-mail: bagnell{at}aesop.rutgers.edu

Matrix metalloproteinases (MMPs) and relaxin (RLX) are reported to play an important role in tissue remodeling and wound repair. When macrophages populate wound sites, they secrete biologically active substances, including MMPs. The transcription factor NF-B is important in MMP gene regulation in macrophage cells. Thus, a monocyte/macrophage cell line, THP-1, was used to study the molecular mechanism of RLX action on MMP-2 and MMP-9 expression. After 24 h incubation with porcine RLX (100 ng/ml), conditioned media (CM) and THP-1 cells were collected. Gelatin zymography demonstrated an increase in pro-MMP-9 activity in response to RLX in CM, and no significant change in pro-MMP-2 expression was observed. Immunoblot analysis also revealed an increase in pro-MMP-9 in CM from RLX-treated THP-1 cells. Gel EMSA showed that NF-B DNA-binding activity was elevated in THP-1 cells treated with RLX for 10 min and reached a peak at 30 min. The NF-B DNA complex was supershifted using antibodies against NF-B subunits p50 and p65. Increased expression of the p50 and p65 NF-B subunits was also detected in THP-1 cells after RLX treatment. Incubation with RLX (90 min) reduced THP-1 expression of the NF-B inhibitor protein, IB-. Using a specific NF-B inhibitor, pyrrolidine dithiocarmate (PDTC) inhibited nuclear binding of NF-B. Pre-exposure to PDTC suppressed pro-MMP-9 activity and protein levels in RLX-treated THP-1 cells. In conclusion, these data suggest that RLX-induced tissue remodeling through increasing MMP-9 expression is dependent on NF-B activation.

Key Words: tissue remodeling • inflammation • macrophage • gelatinase activity