TNF-α binds to the N-terminal domain of fibronectin and augments the β1-integrin-mediated adhesion of CD4+ T lymphocytes to the glycoprotein (original) (raw)
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Immune-inflammatory ffunctions o of ffibroblasts
1994
Inflammation is a response that has evolved over millions of years to become an extremely complex process. This complexity reflects the host's need to deal effectively with a wide variety of potentially injurious agents, as well as the need to incorporate an adequate set of checks and balances. An inappropriately checked response, which occurs rarely, results in disease, either acute or chronic. However, in most instances, inflammation is a beneficial response, essential for survival. Inflammation comprises an extensive network of cellular interactions implemented by an overwhelming number of molecules. One category of signal includes soluble products, such as neuropeptides, lipid mediators, cytokines and growth factors, most of which can be produced by inflammatory/haemopoietic cells. However, resident structural cells can also produce many of these products and, on this basis only, fibroblasts, epithelial, endothelial and smooth muscle cells should be considered as active contributors to the regulation of the inflammatory response. Extracellular matrix (ECM) proteins comprise another category of signals. Whilst the most recognized activities of these proteins are those concerned with providing structural tissue integrity, it is clear that they also have powerful inductive effects. Indeed, ECM proteins can influence the shape, movement and state of activation of inflammatory cells in the tissue. Recent evidence indicates that these signals may also play substantial roles in homing of inflammatory cells to certain sites and in the handling of a number of cytokines and growth factors. In so far as fibroblasts are the main producers of ECM proteins, these new data establish an indirect but important role for fibroblasts in the regulation of the inflammatory response.
Journal of Clinical Investigation, 1992
PBMC express cell surface receptors for extracellular matrix components known as integrins. We have recently shown that ligand binding to one PBMC integrin, the collagen receptor at2fi, stimulates the secretion of interleukin 1 (IL-1). We have now investigated the role of fibronectin (Fn), an adherence protein that has binding sites for both PBMC and collagen, in the generation of the IL-1 response to collagen. In contrast to collagen, Fn did not stimulate IL-1 release but Fn-depleted serum decreased the release of IL-1 induced by collagen. A polyclonal antiserum directed against Fn also decreased the collagen-induced IL-1 secretion. The IL-1 response to collagen from cells incubated in Fn-depleted serum was restored by the addition of either purified Fn or the 120-kD cell-binding fragment of Fn, which contains the cell-binding site but not the collagen-binding domain. Smaller Arg-Gly-Asp (RGD) peptides failed to enhance the PBMC response to collagen but inhibited in a concentration-dependent fashion the potentiating effect Fn. As expected, a MAb against the aci2f collagen receptor decreased collagen-induced IL-1 release. However collagen-induced IL-1 release was also inhibited by a MAb against the a5fl Fn receptor. The effect of the two MAbs was not additive, suggesting that the occupancy of both receptors by ligands is required in order for collagen to induce an maximal response from PBMC. The mechanism by which Fn exerts its effect remains unknown. However, flow-cytometric analysis revealed that Fn does not alter expression of the a2Bi receptor on PBMC. These data demonstrate a potentiating effect of Fn on the collagen-induced secretion of IL-i from human PBMC and suggest that this effect is mediated via the integrin asfi. These findings indicate a complex interactive role for specific integrin receptors in the regulation of the mononuclear cell immune response.
Tumor necrosis factor-α inhibits collagen synthesis in human and rat granulation tissue fibroblasts
Experientia, 1996
The purpose of the study was to examine the effects of tumor necrosis factor-~ (TNF-c0 on collagen gene expression in rat and human granulation tissue fibroblast cultures. The cells were exposed to 0.1, 1, 10, or 100 ng/ml of TNF-~, and the rate of collagen synthesis was measured as synthesis of protein-bound 3H-hydroxyproline. Total cellular RNA was isolated from fibroblasts, and measurements of specific cellular RNAs from fibroblasts were performed by Northern blot hybridizations using 32p-labeled cDNA probes. In cultures of rat granulation tissue fibroblasts TNF-c~ decreased 3H-hydroxyproline production to about 75% of that in controls and it also decreased proc~ 1 (I) and proc~ l(III) collagen mRNA levels, maximally to 33% and 23% of the control levels, respectively. In cultures of human granulation tissue fibroblasts a similar inhibiting effect in the production of collagen was seen. TNF-c~ decreased the production of 3H-hydroxyproline to 56% of the control value with a dose of 100 ng/ml also having an inhibiting effect on proc~ l(I) collagen mRNA levels of up to 43% of the control level. However, no effect was seen on proc~l(III) collagen mRNA levels.
Lymphocyte Extracellular Matrix Interactions
Scandinavian Journal of Immunology, 1989
Limiting dilution analysis was performed in the presence ofinterleukin 2 (IL-2) on lymphocytes isolated from ihf synt>vial fluid (SF) and peripheral bluod (PB) of patients wuh rheumaloid arthritis (RA) and PB of normal donors. Clones of these 'spontaneously' lL-2-rcsponsive cells from PB and SF were compared for their reactivity wiih components of the extracellular matrix (i,c. native or denatured type 1 or type II collagen and proteoglycan). It was determined that all clones from boih PB and SI' were activated to produce interferon (IFN) in Ihe presence of any of the connective lissuc components (CTC), Clones derived from normal PB behaved in a similar fashion but produced lower IFN-y levels. There was a synergy between the CTC and serum or plasma fibronectin. which was more apparent when soluble CTC were used as the stimuli rather than immobilized CTC, The tihroneciin alone was unable to induce IFN-v production under any of the conditions tested (i,c. soluble or immobilii^ed). These results demonstrate ihai clones of IL-2-rcsponsive T cells car be activated by interactions with connective tissue componcnis to prcxluce IFN-y
Monoclonal antibody to fibronectin which inhibits extracellular matrix assembly
FEBS Letters, 1987
A monoclonal antibody L8 specific to fibronectin was shown to inhibit fibronectin incorporation into the fibroblast extracellular matrix. Antibody L8 could not interact with fibronectin complexed with gelatin. The results suggest the existence of a specific site on the fibronectin molecule playing a critical role in the assembly of the fibronectin extracellular matrix. This site is located near the collagen-binding domain.
Evidence that TNF-induced respiratory burst of adherent PMN is mediated by integrin alpha(L)beta(2)
PubMed, 2002
Polymorphonuclear leukocytes (PMN) respond to tumor necrosis factor (TNF) with a respiratory burst (RB) only after adherence to surfaces coated with extracellular matrix proteins such as fibronectin and fibrinogen (permissive substrates) but not with others such as laminin or collagen (nonpermissive substrates). As PMN adherence to both types of surfaces is dependent on beta(2) integrins, we investigated the molecular basis of the different metabolic response to TNF. In particular, we evaluated the relative role of each beta(2) integrin (alpha(L)beta(2), alpha(M)beta(2), and alpha(X)beta(2)) in adherence and O(2)(-) production of PMN residing on fibronectin- and laminin-coated surfaces, which were considered as models of permissive and nonpermissive surfaces, respectively. By using alpha chain-specific monoclonal antibodies (mAb), we show that alpha(M)beta(2) and alpha(X)beta(2) mediate adherence to fibronectin and laminin; alpha(L)beta(2) is not involved in adherence to laminin and has only a minimal contribution in adherence to fibronectin. Furthermore, production of O(2)(-) in response to TNF was induced by immobilized anti-alpha(L)beta(2) but not anti-alpha(M)beta(2) or anti-alpha(X)beta(2) mAb. A strong correlation was also found between expression of alpha(L)beta(2) and TNF-induced RB on fibronectin. Lastly, PMN responded to TNF on laminin with a RB after the inclusion of alpha(L)-specific mAb in the laminin coat. Thus, we conclude that TNF-induced RB by PMN residing on fibronectin is mediated by alpha(L)beta(2) and that alpha(M)beta(2) and alpha(X)beta(2) are likely to play an ancillary role to the signaling activity of alpha(L)beta(2) by facilitating its recruitment to sites of adherence. The nonpermissiveness of laminin appears to be a consequence of its inability to act as a ligand for alpha(L)beta(2).
The Journal of Immunology, 2000
The migration of T cells into extravascular sites of inflammation is regulated by information derived from the molecular structure of the invaded tissue and from chemokine and cytokine gradients in the context of the extracellular matrix (ECM). Although recent studies have highlighted the role of particular chemoattractants in leukocyte migration, to date little is known about how specific combinations of contextual signals control the migration of leukocytes and their localization at sites of inflammation. Here we studied the interplay between a pleiotropic cytokine, TNF-␣, and two prototypic chemoattractants, RANTES and stromal cell-derived factor-1␣ (SDF-1␣), on human CD45RO ؉ T cells migrating within an ECM-like context. For this purpose, we used a newly constructed three-dimensional gel system designed to follow, in real time, the migration of individual leukocytes along chemotactic gradients in vitro. We found that TNF-␣, which binds the ECM protein fibronectin and lacks adhesion-and migration-promoting effects of its own, can act as a proadhesive cytokine on T cells exposed to RANTES and SDF-1␣. Furthermore, fibronectin-complexed TNF-␣ provided anchorage signals to the T cells as they moved directionally along chemoattractive gradients. This effect of TNF-␣ required an intact TNF-␣ receptor II subtype on the migrating T cells. The anchoring effect of TNF-␣ appears to be specific; IL-2, an integrin-activating proadhesive cytokine, does not transmit stoppage signals to T cell migration induced by RANTES. Thus, TNF-␣ present in the ECM at sites of inflammation may function to anchor T cells recruited to these sites by chemotactic signals.
Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, 2007
Joint destruction in arthritis is often associated with high levels of inflammatory cytokines. Previous work has shown that inflammatory conditions can alter the activities of glycosyltransferases that synthesize the glycan chains of glycoproteins, and that these changes in turn can influence the functions of glycoproteins. We therefore examined glycosyltransferases involved in glycoprotein biosynthesis in primary cultures of bovine articular chondrocytes and human chondrocytes isolated from knee cartilage of osteoarthritis patients. Bovine chondrocytes exhibited enzyme activities involved in the synthesis of bi-antennary complex Asn-linked N-glycans, as well as the enzymes involved in the synthesis of GalNAc-Ser/Thr-linked O-glycans with the core 1 structure. Human chondrocytes, in addition, were able to synthesize more complex O-glycans with core 2 structures. TNFα was found to induce apoptosis in chondrocytes, and this process was associated with significant changes in lectin binding to chondrocyte cell surface glycans. TGFβ increased cell proliferation, and had significant effects on cell surface glycosylation in bovine but not in human cells. These cytokine-specific effects were partially correlated with changes in glycosyltransferase activities. Thus, chondrocytes have many of the enzymes necessary for the synthesis of N-and O-glycan chains of glycoproteins. The O-glycosylation pathways and the effects of TNFα and TGFβ on glycosylation differed between bovine and human chondrocytes. These alterations are of potential importance for the regulation of the functions of cell surface receptors on chondrocytes, and for an understanding of the pathophysiology of arthritis.