| The fibronectin matrix is an insoluble fibrillar network that provides an extracellular scaffold to support tissue organization, including appropriate cellular architecture and differentiation status, as well as assembly of the collagenous matrix. Remodeling of the fibronectin matrix occurs during a variety of pathological and regenerative processes. Cellular generated tensional forces can alter the secondary and tertiary structure of the fibronectin matrix and regulate the exposure of cryptic activities that directly impact cell behavior. Not much is known about the biological activity of the unfolded Type III fibronectin modules. Therefore, we have evaluated the effects of the partially unfolded Type III fibronectin module, FnIII-1c, in human dermal fibroblasts. Our data show that FnIII-1c stimulates the activation of p38 MAPK signaling pathway, which is independent of FnIII-1c's effects on fibronectin matrix organization. p38 MAPK activation by FnIII-1c is accompanied by the NFkappaB-dependent increase in the expression of several inflammatory genes, including the cytokines, IL-8 and TNF-alpha via Toll-like receptor 4 (TLR4). These data revealed that cryptic activity within the FnIII-1 module modulates the tissue inflammatory response and suggests that fibronectin matrix remodeling can induce the expression of cytokines by stromal cells present in the tissue microenvironment, providing evidence for a previously unrecognized link between fibronectin matrix remodeling and the regulation of the innate immune system. p38 MAPK and c-Jun NH2-terminal kinase (JNK) pathways coordinately regulate FnIII-1c-induced inflammatory gene expression. JNK signaling pathway regulates FnIII-1c's effect by mediating the phosphorylation of histone H3 at serine 10. p38 MAPK signaling modulates FnIII-1c-induced inflammatory mediators through direct phosphorylation of MK2. Fibronectin is one of the abundant extracellular matrix proteins that are extensively expressed in tumor tissues and able to protect tumor cells from apoptosis (Rintoul et al., 2002; Allen and Louise, 2011). We have revealed that FnIII-1c plays a role on regulating TRAIL-induced apoptosis in human lung cancer cells, as it is able to attenuate TRAIL-induced activation of caspase cascades and trigger the pro-survival signals, which include the activation of NFkappaB, JNK, and p38 MAPK.;Our studies have dissected FnIII-1c's effects on fibronectin matrix from its effects on the activation of intracellular signaling, elucidated the mechanism by which unfolding of fibronectin Type III-1 domain regulates inflammatory response in tissue microenvironment and clarified how local mechanical properties within tissue microenvironment may protect tumor cells from therapeutic treatment. These data may provide potential novel targets for therapies of human cancer and inflammatory diseases. |
