Native and fragmented fibronectin oppositely modulate monocyte secretion of MMP-9.
Monocytes remodel the extracellular matrix (ECM) by secreting proteins composing the ECM such as fibronectin (FN) and degrading proteases such as matrix metalloproteinase-9 (MMP-9), which cleaves FN into fragments. The effects of FN and its fragmented products on the expression of monocyte MMP-9 are controversial and largely unknown. We showed that in human monocytes, the proinflammatory cytokine TNF-alpha induced MMP-9 secretion and increased fragmentation of FN into distinct fragments. When primary monocytes or the U937 monocytic cell line were incubated on a plastic substrate, plastic-coated with native FN, and plastic-coated with fragmented FN (frag-FN), native FN inhibited TNF-alpha-induced proMMP-9 secretion by twofold (P<0.01) compared with plastic or frag-FN. Exploration of the dynamics of inflammation by incubating cells sequentially on the three substrates showed that frag-FN opposed the inhibitory effect of native FN. Inhibition of proMMP-9 by native FN was exerted at the translational level, as no change in MMP-9 mRNA, intracellular protein accumulation, or proteomic degradation was observed, and when degradation was blocked, no de novo translation of MMP-9 could be measured. We also showed that the reduction of MMP-9 secretion by native FN was responsible for attenuated migration of U937 cells (P<0.05). We suggest that in the inflammatory tissue, intact, native FN has a homeostatic role in harnessing MMP-9 activity. However, as fragmented products accumulate locally, they alleviate the inhibition and enable faster migration of the monocytes through the degraded ECM.
Marom
Barak
B
Immunology Research Unit, Carmel Medical Center, 7 Michal St., Haifa, 34362, Israel.
Rahat
Michal A
MA
Lahat
Nitza
N
Weiss-Cerem
Lea
L
Kinarty
Amalia
A
Bitterman
Haim
H
D002448:Cell Adhesion; D002465:Cell Movement; D002478:Cells, Cultured; D005353:Fibronectins / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D009000:Monocytes / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology
D005353:Fibronectins; D014409:Tumor Necrosis Factor-alpha; D020780:Matrix Metalloproteinase 9