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PubMed2002

Complexities in ETS-domain transcription factor function and regulation: lessons from the TCF (ternary complex factor) subfamily. The Colworth Medal Lecture.

The ETS-domain transcription factor family can be divided into a series of subfamilies. Elk-1 represents the founding member of the ternary complex factor (TCF) subfamily. By focusing on the TCF subfamily, we can demonstrate the complexities that exist in the function and regulation of ETS-domain transcription factors. This article focuses on Elk-1 in detail and summarizes the functions of other TCFs. The key themes covered include the domain structure of the TCFs, the mechanisms of complex formation with serum response factor, regulation of TCFs by mitogen-activated protein kinase cascades, and transcriptional regulatory properties of the TCFs. Finally, the emerging role of the TCFs in vivo is discussed. A picture is developing indicating that, while these proteins exhibit significant sequence and functional conservation, key differences in their structure and regulation are being identified which may relate to unique functions of these proteins in vivo.

Amino Acid Sequence↗
PubMed1992

Migration of a human keratinocyte cell line (HACAT) to interstitial collagen type I is mediated by the alpha 2 beta 1-integrin receptor.

The migratory response of the human keratinocyte cell line HaCaT to collagen type I and the molecular mechanism underlying collagen-mediated migration have been analyzed. The migratory response of HaCaT cells to collagen type I consisted of a dose-dependent migration to insoluble step gradients of substratum-bound collagen (haptotaxis) and to gradients of soluble collagen (chemotaxis). Checkerboard analysis demonstrated a minor chemokinetic component. Denatured collagen type I was less chemoattractive than the native triple-helical form. Pre-treatment of cells with 25-250 micrograms/ml of synthetic peptides containing the fibronectin cell-recognition sequence RGD (Arg-Gly-Asp) resulted in a concentration-dependent inhibition of fibronectin-mediated chemotaxis, whereas chemotaxis to collagen was not affected. We then investigated the role of VLA/collagen-receptors for collagen type I-induced chemotaxis. Monoclonal antibody (MoAb) 5E8, which selectively blocks function of the alpha 2 subunit of the VLA-2/collagen receptor, dose-dependently inhibited the chemotactic response of HaCaT cells to collagen. This effect was specific for collagen-mediated chemotaxis because the chemotactic response to fibronectin remained unaffected. In contrast, a function blocking MoAb directed to the alpha 3 subunit of the coexpressed VLA-3 receptor, which is also capable of binding collagen, had no effect. However, function blocking MoAb directed to the beta 1-chain of integrins completely inhibited chemotaxis to collagen type I. Based on our results, we propose that the chemotactic migration of the human keratinocyte cell line (HaCaT) to collagen type I is specifically mediated by the RGD independent VLA-2/collagen receptor (alpha 2 beta 1) of the integrin family.

Amino Acid Sequence↗
PubMed1990

cDNA sequence of the human integrin beta 5 subunit.

A novel integrin receptor involved in cell adhesion to the matrix protein vitronectin has recently been described from a human lung epithelial-derived cell line (Cheresh, D. A., Smith, J. W., Cooper, H. M., and Quaranta, V. (1989) Cell 57, 59-69). This receptor has an alpha subunit that appears identical to the alpha v of the vitronectin receptor alpha v beta 3 expressed in melanoma and endothelial cells, but is complexed with a distinct beta subunit, beta 5. cDNA clones coding for beta 5 have been isolated and used to determine the mRNA and amino acid sequence of this new subunit. A 3.3-kilobase mRNA was found to code for a mature protein of 775 amino acid residues with a hydrophobic leader sequence of 24 amino acids. A 56% identity was found between the beta 5 and beta 3 protein sequences, making them the most closely related of the integrin beta subunits. Polymerase chain reaction abundance analysis revealed that alpha v and beta 5 mRNAs were found in seven very different cell lines, compared with beta 3 mRNA which was found in only three of the them, indicating that this new integrin receptor may be widely distributed.

Amino Acid Sequence↗
PubMed1995

Expression of vitronectin receptor on human NK cells and its role in protein phosphorylation, cytokine production, and cell proliferation.

In this paper, we provide evidence that the vitronectin receptor (VNR) alpha v beta 3 is expressed on human NK cells. The presence of this VNR on freshly purified NK cells was demonstrated by flow cytometry analysis, as well as biochemically, after 125I-labeled surface lactoperoxidase labeling and immunoprecipitation. mAbs LM142 and LM609 specific for alpha v and alpha v beta 3, respectively, precipitated a heterodimer of alpha- and beta-chains with approximate molecular masses of 155 and 110 kDa under nonreducing conditions. Under reducing conditions, there was an apparent decrease in the molecular mass of the alpha-chain, which is likely to result from the release of a protein of 20 to 30 kDa linked by internal disulfide bond to the alpha v-chain. Integrin alpha v beta 3 expressed on NK cells became functional, i.e., was able to bind its ligand, vitronectin (VN), only after cellular activation or when costimulation with an additional signal was provided. Thus, NK cells adhered to plastic-immobilized VN only after IL-2 activation, and RGD-containing synthetic peptides or mAbs specific for alpha v beta 3 complex inhibited this binding. To assess the role of the VNR in signal transduction, anti-beta 3 mAb was used to cluster the VNR on NK cells and, thereby, mimic the process that occurs during formation of adhesive contacts. Cross-linking of VNR on fresh NK cells stimulated phosphorylation on tyrosine residues of several intracellular proteins. The major increase in tyrosine phosphorylation was observed in proteins of approximate molecular masses of 75 and 120 kDa. Therefore, signal transduction by the VNR on NK cells induced activation of intracellular protein kinases. Ligand engagement of the VNR on NK cells also costimulated cytokine production and proliferation of NK cells. Binding of NK cells to plastic-immobilized VN served as a costimulus with either anti-Fc gamma RIII or IL-2 to produce IFN-gamma, TNF-alpha, and cell proliferation. Our findings suggest that occupancy and subsequent clustering of VNRs play a role in the activation and function of human NK cells.

Amino Acid Sequence↗
PubMed1997

Ectodomain interactions of leukocyte integrins and pro-inflammatory GPI-linked membrane proteins.

Although glycosylphosphatidyl-inositol (GPI) linked membrane proteins do not possess transmembrane or cytosolic sequences they elicit transmembrane signals. Using microscopic fluorescence imaging and resonance energy transfer (RET) techniques we have shown that certain pro-inflammatory GPI-linked membrane proteins can interact with leukocyte beta 2 integrins (complement receptor type 3 (CR3) and 4 (CR4) and the leukocyte function-associated antigen-1 (LFA-1)). For example, physical associations between CR3 and Fc gamma RIIIB, CR3 and urokinase receptors, and CR3 and CD14 (lipopolysaccharide receptor) have been found. Although Fc gamma RIIIB appears to be constitutively associated with CR3, urokinase receptors and CD14 associations with CR3 are influenced by their ligation status and cell function (e.g. adherence and locomotion). CR3-to-urokinase receptor interactions have been confirmed by immunoprecipitation techniques. Immunoprecipitation of CR3 from Brij-58 lysates after biotinylation of neutrophil membranes revealed proteins of M(r) = 40,000, 50,000, 74,000 and 120,000, in addition to bands corresponding to the integrin alpha and beta chains. Cell functions such as transmembrane signaling and superoxide release/priming have been linked to these interactions. Importantly, reagents that affect the lectin-like site of CR3, such as N-acetyl-D-glucosamine, alpha-methyl-D-mannoside and beta-glucan alter these interactions and, in parallel, leukocyte functions. Thus, the interactions of GPI-linked proteins and integrins can be highly dynamic events linked to cell activities. Our studies suggest that it may be possible to develop new drugs directed at the lectin-like site of beta 2 integrins that block GPI-linked protein-to-integrin coupling thereby controlling inflammatory cell processes including cell adherence, locomotion and activation. Such drugs may be useful in clinical conditions such as ischemia-reperfusion injury, sepsis, arthritis and others.

CD18 Antigens↗
PubMed1990

Participation of CD11a-c/CD18 and RGD-recognizing adhesion molecules in the binding of LGL to fibroblasts. Evidence for the role of CD11a in the fibroblast-mediated inactivation of NK cells.

We have previously shown that large granular lymphocytes (LGL) are inactivated by contact with natural killer (NK) resistant monolayer target cells. In this work we have analysed which adhesion molecules are involved in the binding of LGL to such targets, as exemplified by fibroblasts, and in the subsequent inhibition of their NK activity. The results indicate that antibodies against CD54 (intercellular adhesion molecule 1, ICAM-1), CD11a (leucocyte function antigen 1, LFA-1, alpha chain), and CD18 (common beta chain of the beta 2-integrin family) significantly (by 50%) reduce the binding of LGL onto inhibitory target cells. The matrix protein-based synthetic peptide RGD and anti-CD29 (the common beta chain of the beta 2-integrin family) antibodies also diminish the binding (by 35%). The effects of the antiadhesion molecule antibodies and the peptide are additive, the combination of both leading to an almost complete block of adhesion. It may be hypothesized that some of the binding-relevant adhesion molecules of the RGD-binding domain on LGL (CD29) may be involved in the delivery of the inactivating signal to the effector cell. Indeed, incubation of LGL with anti-CD11a antibodies, but neither with antibodies against other binding-relevant epitopes nor with RGD, significantly reduced their NK activity. The mechanism of the inactivation was similar to that induced by intact NK-resistant target cells. On the basis of the present results we suggest that the CD11a molecule is involved in the down-regulation of the NK activity of peripheral blood lymphocytes.

Antibodies, Monoclonal↗
PubMed1995

Cell spreading in Colo 201 by staurosporin is alpha 3 beta 1 integrin-mediated with tyrosine phosphorylation of Src and tensin.

Staurosporin, a broad-spectrum kinase inhibitor, induced cell spreading in a human colon cancer cell line, Colo 201. On collagen and laminin, cell spreading was induced in more than 90% of the cells and was dependent on very late activation antigen-3, as shown by an antibody inhibition assay. Cell spreading required divalent cations and showed the order of preference Mn2+ > Mg2+ > Ca2+. On fibronectin, only about 30% of the cells were observed to spread, and spreading occurred via a non-integrin, RGD-independent pathway. Staurosporin-induced spreading was inhibited by treatment with tyrosine kinase inhibitors herbimycin A and methyl 2,5-dihydroxycinnamate. Despite the presence of staurosporin, seven proteins (220, 175, 150, 98, 62, 58, and 45 kDa) showed increased levels of tyrosine phosphorylation in association with cell adhesion. Two of these (58 and 220 kDa) were identified by immunoprecipitation as Src product and tensin, respectively. Flow cytometric analysis showed that the Colo 201 cells expressed the alpha 2, alpha 3, alpha 6, and beta 1 chains of integrin, but expression of these chains was not influenced by staurosporin. Immunofluorescence microscopy revealed that the alpha 3 chain, diffusely expressed on the cell surface in the absence of staurosporin, was concentrated at focal adhesion plaques after staurosporin treatment. Neither alpha 2 nor alpha 6 was focalized by the treatment.

Alkaloids↗
PubMed2000

Angiotensin II enhances integrin and alpha-actinin expression in adult rat cardiac fibroblasts.

Angiotensin II (Ang II) plays an important role in cardiac remodeling through stimulation of proliferation and extracellular matrix (ECM) production in cardiac fibroblasts. Integrins are a family of transmembrane receptors that mediate the attachment of cells to ECM. We hypothesized that Ang II regulation of integrins further contributes to its role in cardiac remodeling. We cultured adult rat cardiac fibroblasts with and without Ang II (100 nmol/L) to determine the effects on mRNA and protein levels of integrins, as well as alpha-actinin and other cytoskeletal proteins that link to integrins at the site of focal adhesions. Ang II was also added in the presence of irbesartan (10 micromol/L), a specific Ang II type 1 (AT(1)) receptor antagonist, or PD 123319 (10 micromol/L), a specific Ang II type 2 receptor antagonist. To investigate the function of these integrins, we determined the effects of blocking antibodies on Ang II-induced adhesion to ECM. We also treated spontaneously hypertensive rats (SHR) with an AT(1) receptor blocker, losartan, or with hydralazine to investigate integrin and alpha-actinin expression in treated and untreated SHR. Ang II enhanced alpha(v), beta(1), beta(3), and beta(5) integrins; osteopontin; and alpha-actinin mRNA and protein levels in cardiac fibroblasts. All of these effects were inhibited by irbesartan but not by PD 123319. Pretreatment of cardiac fibroblasts with Ang II enhanced cell attachment to ECM proteins and induced focal adhesion kinase phosphorylation. Blocking antibodies to beta(3) and alpha(v)beta(5) attenuated Ang II-induced adhesion. In SHR, ventricular alpha(v) and beta(5) integrin expression and alpha-actinin were increased compared with those in Wistar-Kyoto rats. Although both losartan and hydralazine lowered mean arterial pressure and decreased peripheral vascular resistance, only losartan attenuated the increased integrin, alpha-actinin, fibronectin laminin, and osteopontin expression and the increased left ventricular mass (as determined with echocardiography). Hydralzine had none of these effects. Although both agents attenuated beta-myosin heavy chain expression, a marker of hypertrophy, losartan had a greater effect. These results suggest that integrins and alpha-actinin are upregulated by Ang II and in left ventricular hypertrophy and that the block of expression of these proteins through inhibition of the AT(1) receptor is associated with attenuation of the hypertrophic response. Ang II induces integrin and alpha-actinin expression in cardiac fibroblasts that is associated with adhesion and left ventricular hypertrophy and blocked through inhibition of the AT(1) receptor.

Actinin↗
PubMed1993

[Pattern of expression of integrins in alveolar epithelia of fetal and adult lungs and interstitial lung diseases].

We studied the expression of integrin alpha and beta chains on alveolar epithelia in normal and fibrotic lung tissue by immunohistochemistry. Alveolar epithelia and their precursor cells in fetal lung tissue consistently expressed alpha 1, alpha 2, alpha v and beta 1 chains. Neoexpression of alpha 4, alpha 6 and beta 4 chains was detected on alveolar epithelia of fibrotic lung tissue. Adhesion blocking assays with isolated type II pneumocytes were performed to investigate the substrate specificity of the alpha chains. alpha 1, alpha 2 and alpha 3 demonstrated a specificity for collagen, alpha 4, alpha 5 and alpha 6 for fibronectin, alpha 3 and alpha 6 for laminin and finally alpha 5 and alpha v for vitronectin.

Adult↗
PubMedDate not supplied

Induction of adhesion molecules on the endothelia of rejecting cardiac allografts.

BACKGROUND: Adhesion of leukocytes to vascular endothelium and their migration from the circulation into underlying tissue is regulated by an array of inducible cell adhesion molecules. We determined the kinetics and expression patterns of adhesion molecules expressed by the endothelia of rat cardiac allografts including the following: major histocompatibility complex class II (OX6), intercellular adhesion molecule-1 (1A29), vascular cell adhesion molecule-1 (5F10), leukocyte function-associated antigen-1 alpha-chain (WT.1), the common beta-chain of beta 2 integrins (WT.3), and very late activation antigen-4 (HP2.1) on inflammatory cells. METHODS: Intraabdominal heterotopic cardiac allografts (n = 12) were transplanted from the dark agouti (DA) rats (AG-B4, RT1a) to the Wistar-Furth (WF) rats (AG-B2, RT1v) strain and syngeneic controls (n = 12) were transplanted from dark agouti rat donors to dark agouti rat recipients. The grafts were removed 1, 3, and 5 days after transplantation, and cryostat sections were prepared for indirect immunoperoxidase staining with monoclonal antibodies. The intensity of adhesion molecule expression was scored from 0 to 3 in a blind review. RESULTS: In nontransplanted dark agouti rat hearts, intercellular adhesion molecule-1 was constitutively expressed at a low level on capillary (0.5 +/- 0.5) and postcapillary venular (0.5 +/- 0.2) endothelia. In syngeneic controls, the expression of intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 was also faint and not induced, but a clear induction of class II expression was found on capillary endothelia. Large vessels stained negative for adhesion molecules. In allografts, intercellular adhesion molecule-1 and vascular cell adhesion molecule-1, but not class II, were significantly upregulated on capillary endothelia (p < 0.05). On postcapillary venular endothelia, a distinct induction (p < 0.05) of all three molecules was observed during acute rejection 5 days after transplantation. Concomitantly, the inflammatory leukocytes expressed high levels of leukocyte function-associated antigen-1 alpha-chain and beta-chain in the perivascular space. The expression of very late activation antigen-4 by lymphocytes was, however, nonexistent. In allograft arteries and arterioles, class II and vascular cell adhesion molecule-1, but not intercellular adhesion molecule-1, were weakly expressed during acute rejection. CONCLUSIONS: Our results suggest that postcapillary venular endothelia may be the major site for leukocyte extravasation during acute cardiac allograft rejection in the rat model.

Abdomen↗
PubMed2005

Emerging views on integrin signaling via Rac1 during invasin-promoted bacterial uptake.

Enteropathogenic Yersinia species encode invasin, which promotes uptake into host cells by binding beta1 integrins. Invasin may cluster integrin heterodimers extracellularly and cause the integrin alpha and beta chains to splay apart in the cytoplasm. Cdc42 signaling is not essential for Yersinia uptake, whereas invasin crucially triggers Rac1-mediated signals that enable internalization. The signals linking invasin-mediated adhesion to Rac1 activation are not clear, but a novel kinase may release it from RhoGDI so that Rac1 can be activated, for example by Dock180. Rac1 may act via Arp2/3, phosphatidylinositol 4,5-bisphosphate and capping-proteins in the formation of nascent phagosomes during Yersinia uptake.

Adhesins, Bacterial↗
PubMed1994

Distribution of integrin subunits in normal human kidney.

We evaluated on serial sections the distribution of a large number of integrin alpha and beta chains in normal adult human kidney: 1) the beta 1 chain and its corresponding alpha subunits (alpha 1, alpha 2, alpha 3, alpha 4, alpha 5, alpha 6), 2) alpha v and beta 3 chains, 3) the beta 2 chain and its corresponding alpha chains (alpha X, alpha M, alpha L), and 4) the beta 4 chain. We also evaluated ICAM-1, VCAM and ELAM and the major extracellular matrix components (ECM). A three step immunoperoxidase technique was used on frozen sections. Each cell of the kidney shows a specific distribution of these molecules. The relation with ECM and some of their ligands was evaluated. This immunohistochemical study shows that there is no strict colocalisation of a given ECM component with its specific receptor.

Adult↗
PubMed1991

Effect of biological surfaces on neutrophil O2- production and its relationship to the CD11b/CD18 integrin-dependent adherence.

The production of O2- in response to LPS, PAF, FMLP, TNF and PMA by human neutrophils in suspension and residing on surfaces coated with fetal calf serum (FCS), fibronectin (FN), laminin (LM), collagen types I and IV (CI and CIV), fibrinogen (FBG) or fibrin (FBN) was studied. Of the agonists used, PAF and LPS failed to induce a response in any of the above conditions; FMLP and PMA stimulated neutrophils to produce similar amounts of O2- either in suspension or on biological surfaces; TNF induced O2- production only by cells residing on FN, FBG and FBN. These results indicate that production of oxygen-derived free radicals by neutrophils depends on the type of agonist and the nature of the surface they interact with. The relationship between the respiratory burst and adherence was studied by measuring O2- release and adherence of neutrophils residing on FN, LM, CIV, and FBG, in the absence and in the presence of the monoclonal antibody 60.3 that recognizes the common beta-chain of CD11/CD18 integrins. FMLP, PMA and TNF increased neutrophil adherence on all these surfaces except CIV. The monoclonal antibody markedly inhibited the FMLP and PMA-induced adherence but had no effect on the O2- release elicited by these two agonists. In contrast, the monoclonal antibody inhibited both the increased adherence and O2- release induced by TNF on FN and FBG. The TNF-induced increase in adherence to LM, that was not accompanied by an increase in O2- release, was also inhibited by the monoclonal antibody. We conclude that the respiratory burst of neutrophils residing on surfaces is not necessarily correlated with adherence.

Antigens, CD↗
PubMed1999

Definition of an unexpected ligand recognition motif for alphav beta6 integrin.

Integrin interactions with extracellular matrix proteins are mediated by brief oligopeptide recognition sequences, and synthetic peptides containing such sequences can inhibit integrin binding to the matrix. The RGD peptide motif is recognized by many integrins including alphav beta6, a specific receptor for fibronectin thought to support epithelial cell proliferation during wound healing and carcinoma progression. We report here the discovery of an unexpected non-RGD recognition motif for integrin alphav beta6. We compared the recognition profiles of recombinant alphav beta6 and alphav beta3 integrins by using phage display screening employing 7-mer and 12-mer peptide libraries. As predicted, phages binding strongly to alphav beta3 contained ubiquitous RGD sequences. However, on alphav beta6, in addition to RGD- containing phages, one-quarter of the population from the 12-mer library contained the distinctive consensus motif DLXXL. A synthetic DLXXL peptide, RTDLDSLRTYTL, selected from the phage sequences (clone-1) was a selective inhibitor of RGD-dependent ligand binding to alphav beta6 in isolated receptor assays (IC50 = 20 nM), and in cell adhesion assays (IC50 = 50 microM). DLXXL peptides were highly specific inhibitors of alphav beta6-fibronectin interaction as synthetic scrambled or reversed DLXXL peptides were inactive. NH2- and COOH-terminal modifications of the flanking amino acids suggested that the preceding two and a single trailing amino acid were also involved in interaction with alphav beta6. The DLXXL sequence is present in several matrix components and in the beta chain of many integrins. Although there is as yet no precise biological role known for DLXXL, it is clearly a specific inhibitory sequence for integrin alphav beta6 which has been unrecognized previously.

Amino Acid Sequence↗
PubMed1990

Tumor cell adhesion to frozen lymph node sections--a correlate of lymphatic metastasis in breast carcinoma models of human and rat origin.

The role of tumor cell adhesion in lymphatic metastasis of breast cancer was investigated in vitro using a rat mammary carcinoma model of four cell lines with different metastatic phenotypes, two human breast cancer cell lines, and cryostast sections of normal rat or human lymph nodes, respectively. A positive correlation was found between the adhesion levels obtained with three metastatic rat mammary cell lines (TMT-081 greater than MT-100M & TMT-50) and a non-metastatic line MT-W9B, the latter being 3-4 fold less adhesive to the lymph node sections than the metastatic tumors. This selective adhesion was specific, as it was not found with cryostat sections of rat liver and brain. Enzyme assays indicated that cell surface glycoproteins bearing terminal beta-galactoside residues were involved in the adhesion of the rat tumors. Adhesion of the human breast carcinoma cells Hs578T to sections of human lymph nodes was significantly higher than that of the normal breast epithelial cell line Hs578Bst, and comparable to adhesion of a second breast carcinoma line, MCF-7. Moreover, Hs578T cells isolated from regional lymph nodes of tumor-bearing nude mice were significantly more adhesive to human lymph node sections than the parental line. Adhesion of both human and rat tumors could be partially blocked by the addition of the synthetic peptide GRGDSPK and by antibodies directed to the beta 1 chain of integrin, suggesting that an integrin receptor may played a role in the adhesion. The results suggest that tumor cell adhesion to cryostat sections of lymph nodes is a correlate of the malignant phenotype in mammary tumors of diverse origins, and could be used to delineate the adhesion factors mediating lymphatic metastasis.

Animals↗
PubMed1998

Adhesion molecule expression in erythema nodosum-like lesions in Behçet's disease. A histopathological and immunohistochemical study.

Behçet's (BD) is a systemic inflammatory disease with histological evidence for vasculitis. Leucocyte-leucocyte and leucocyte-endothelial cell interactions are critical in inflammatory reactions that are influenced by the expression, activation and shedding of adhesion molecules. We investigated the expression of some adhesion molecules (E- and L-selectin, VLA-4, ICAM-1, PECAM-1, VCAM-1 and CD18 and CD11c chains of beta-2 integrins) on endothelial and inflammatory cells by immunohistochemistry on cryostat sections of erythema nodosum lesions taken from 15 patients with BD and 12 patients with erythema nodosum of unknown cause. Hematoxylin-eosin stained sections of all specimens were also assessed. The major histopathological findings were perivascular mononuclear cell infiltration and secondary vasculitic changes with no difference between the two groups (P > 0.05). However, the frequency of thrombophlebitis was higher in BD (P < 0.001). Endothelial and inflammatory cell adhesion molecule expression did not show any significant difference between groups (P > 0.05). Although VCAM-1 expression and intensity on endothelial cells of BD patients seemed to be lower, this did not reach statistical significance (P = 0.056). We concluded that subcutaneous thrombophlebitis is an important feature of erythema nodosum like lesions in BD, which is almost impossible to understand by physical examination alone. Colchicine, which is known to have some influence on adhesion molecules, might have affected our results, as these showed no significant difference regarding adhesion molecules between the two groups.

Adult↗
PubMed1993

In vitro stimulation of polymorphonuclear cell adhesion by ribomunyl and antibiotic + ribomunyl combinations: effects on CD18, CD35 and CD16 expression.

Several functions of polymorphonuclear cells (PMNs) require adhesion to occur. Various membrane proteins' functions such as CD18 (beta 2 chain of integrin), CD35 (CR1) and CD16 (F c gamma Receptor III) participate in adhesion. In vivo treatment with Ribomunyl (R), an immunomodulating agent, was shown to enhance adhesion and migration of PMNs. To explore the direct effect of R on PMNs, cells from healthy subjects were treated in vitro with R. A significant increase of PMN adhesion and expression of CD18 and CD35 molecules were observed with 50 and 100 micrograms/ml of R after 2 h incubation. However, R-treatment decreased the PMN reactivity towards anti-CD16 (F c gamma RIII) monoclonal antibody. The effect of R on adhesion and membrane molecule expression was independent of the presence of serum and of polymixin B. Thus, this effect cannot be due to lipopolysaccharide (LPS) contaminants and does not require interactions with serum components. In previous studies, it was shown that in vitro amoxicillin increased some PMN functions whereas josamycin decreased them. The in vitro incubation of PMNs with R and amoxicillin (100 micrograms/ml) potentiated the positive effect of amoxicillin on adhesion and the antibiotic counterbalanced the negative effect of R on CD16 expression. In addition, R compensated the negative effect of josamycin (100 micrograms/ml) on PMN adhesion and on CD18 and CD35 expression. This study indicates: (1) the direct effect of R on PMN adhesion and on expression of molecules involved in adhesive-mediated functions, and (2) the beneficial effect of the association of R with antibiotics which can stimulate PMN activity.

Adjuvants, Immunologic↗
PubMed2002

A conserved interaction between beta1 integrin/PAT-3 and Nck-interacting kinase/MIG-15 that mediates commissural axon navigation in C. elegans.

BACKGROUND: Integrins are heterodimeric (alphabeta) transmembrane receptors for extracellular matrix (ECM) ligands. Through interactions with molecular partners at cell junctions, they provide a connection between the ECM and the cytoskeleton and regulate many aspects of cell behavior. A number of integrin-associated molecules have been identified; however, in many cases, their function and role in the animal remain to be clarified. RESULTS: We have identified the Nck-interacting kinase (NIK), a member of the STE20/germinal center kinase (GCK) family, as a partner for the beta1A integrin cytoplasmic domain. We find that NIK is expressed in the nervous system and other tissues in mouse embryos and colocalizes with actin and beta1 integrin in cellular protrusions in transfected cells. To demonstrate the functional significance of this interaction, we used Caenorhabditis elegans, since it has only one beta (PAT-3) integrin chain, two alpha (INA-1 and PAT-2) integrin chains, and a well-conserved NIK ortholog (MIG-15). Using three methods, we show that reducing mig-15 activity results in premature branching of commissures. A significant aggravation of this defect is observed when mig-15 activity is compromised in a weak ina-1 background. Neuronal-specific RNA interference against mig-15 or pat-3 leads to similar axonal defects, thus showing that both mig-15 and pat-3 act cell autonomously in neurons. Finally, we show a genetic interaction between mig-15, ina-1, and genes that encode Rac GTPases. CONCLUSIONS: Using several models, we provide the first evidence that the kinase NIK and integrins interact in vitro and in vivo. This interaction is required for proper axonal navigation in C. elegans.

Actins↗