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PubMed1999

Detection of soluble alpha1 integrin in human serum.

An enzyme-linked immunosorbent assay (ELISA) for the detection and quantitation of soluble alpha1beta1 integrins (salpha1) in human serum samples was developed. Solid phase-bound anti-alpha1 integrin monoclonal antibody (mAb) TS2/7 was used to capture salpha1, and mAb 1B3.1 was used to detect the immobilized integrin. An extract of human placenta (PE) containing 340 ng/mL of VLA-1 molecules served as a positive control, and serum samples from normal donors and patients were assayed. Optimal binding of anti-alpha1 integrin mAb 1B3.1, expressed as specific optical density (OD), was obtained when a 5 microng/mL solution of anti-alpha1 integrin "capture" mAb TS2/7 was immobilized to the wells and the PE was added. Solutions of albumin or collagen, in contrast, did not result in binding, confirming the specificity of the assay for sal. Furthermore, the specific OD of the wells correlated directly with the concentration of PE. A concentration of salpha1 above that of a 1:100 dilution of PE--that is, >3.4 ng/mL of integrin, in which the intra-assay correlation of variance was <5.7%, was found in 5 of 8, 3 of 8, and 6 of 9 serum samples from normal individuals, patients with connective tissue diseases (CTD), and patients with liver diseases (LD), respectively. These results suggest, for the first time, that salpha1 are present in healthy and diseased human serum.

Adult↗

PubMed2001

Distribution of the collagen-binding integrin alpha10beta1 during mouse development.

We have previously identified and characterised the collagen type II-binding integrin subunit alpha10, which is a member of the beta1 family and is expressed by chondrocytes. In the present study, we examined the expression of the alpha10 integrin in various mouse tissues. Immunohistochemical analysis of alpha10 on cryosections from 3-day-old mice demonstrated that alpha10beta1 was present in the hyaline cartilage of joints, vertebral column, trachea and bronchi. In addition, alpha10 was found in the ossification groove of Ranvier, in the aortic and atrioventricular valves of the heart and in the fibrous tissue lining skeletal muscle and ligaments. Overall, the distribution was distinct from that of the collagen-binding integrins alpha1beta1 and alpha2beta1. We also found that alpha10beta1was the dominating collagen-binding integrin during cartilage development. Expression of alpha10 appeared at embryonic day 11.5 (E11.5) at the same time as chondrogenesis started as judged by collagen type II expression. At E13.5, alpha10 was present throughout the anlage as well as in the perichondrium and in mesenchyme just outside the perichondrium, where it localised with collagen type I. Four weeks after birth, alpha10 was prominent both at the articular surface and in the growth plate. In conclusion, we found that integrin alpha10beta1 was a major collagen-binding integrin during cartilage development and in mature hyaline cartilage. In addition, we found that alpha10beta1 was present in some fibrous tissues.

Animals↗

PubMed2000

Human renal fibroblast contraction of collagen I lattices is an integrin-mediated process.

BACKGROUND: Expression of the beta1 family of integrins allows dermal fibroblasts in wounds to contribute to the healing process through migration, adhesion, synthesis, and rearrangement of extracellular matrix. To date the ability of human renal fibroblasts to reorganize collagens and the role of cell surface receptors in this process remain unknown. METHODS: Renal fibroblasts were grown from the cortical tissue of surgically removed human kidneys. The ability of human renal fibroblasts to reorganize interstitial collagen I was examined in vitro using solidified collagen I lattices. Integrin function was blocked by incubating fibroblasts with isotype-specific antibodies prior to addition to collagen I lattices. RESULTS: Human renal fibroblasts embedded in collagen I lattices progressively decreased lattice diameter to 60.6+/-11.4% of initial diameter at 48 h post-release (P:<0.01). Fibroblasts incubated in the presence of antibody to beta1 integrin failed to contract collagen I lattices, whilst fibroblasts incubated with non-specific antibody reduced lattice diameter to 60.1+/-12.4% of initial diameter at 48 h post-release (P:<0.01). Further characterization of integrin alpha subunits showed that blocking alpha2beta1 integrin prevented lattice contraction (P:<0.05, alpha2beta1 integrin antibody vs non-specific antibody), whilst blocking of alpha5beta1, alpha3beta1 and alpha1beta1 integrins did not influence this process. CONCLUSIONS: We postulate that collagen I fibril rearrangement by human renal fibroblasts in vitro appears to be an integrin-mediated process involving the alpha2beta1 integrin.

Adult↗

PubMed2006

Developmental and injury-induced expression of alpha1beta1 and alpha6beta1 integrins in the rat spinal cord.

Loss and damage to blood vessels are thought to contribute to secondary tissue loss after spinal cord injury. Integrins might be therapeutic targets to protect the vasculature and/or promote angiogenesis, as their activation can promote tubule formation and survival of endothelial cells in vitro. Here, we show that immunostaining with an antibody against the alpha1beta1 integrin heterodimer is present only in blood vessels from postnatal day 1 (P1) through adulthood in Sprague-Dawley rats. After a spinal cord contusion at T9 in adults, the area of alpha1beta1 integrin positive blood vessels increases within 11 mm from the injury site at 3 days post-injury and remains prominent within the injured core only at 7 days. Staining for the alpha6beta1 integrin heterodimer increases in blood vessels between P10 and adulthood and is present in preganglionic neurons of the intermediolateral cell column (IML) at all ages. The alpha6beta1 integrin is also expressed by motor neurons postnatally, and oligodendrocyte precursors (OPCs), as previously reported. After the contusion, the area of alpha6beta1-stained blood vessels is increased at 3 days and most prominently, 1 mm from the injury site, followed by a significant reduction at 7 days, when alpha6beta1 integrin staining is most prominent around the injured core. Staining is also present in a subset of microglia and/or macrophages. These results raise the possibility that alpha1beta1 and alpha6beta1 integrins in blood vessels might be targeted to reduce blood vessel loss and promote angiogenesis, which may promote tissue sparing after spinal cord injury.

Age Factors↗

PubMed2005

Evidences that beta1 integrin and Rac1 are involved in the overriding effect of laminin on myelin-associated glycoprotein inhibitory activity on neuronal cells.

During neurite elongation, migrating growth cones encounter both permissive and inhibitory substrates, such as laminin and MAG (myelin-associated glycoprotein), respectively. Here, we demonstrated on two neuronal cell lines (PC12 and N1E-115), that laminin and collagen hampered, in a dose-dependent manner, MAG inhibitory activity on several integrin functions, i.e., neurite growth, cell adhesion and cell spreading. Using a function blocking antibody, in PC12 cells, we showed that alpha1beta1 integrin is required in these phenomena. In parallel, we observed that MAG perturbs actin dynamics and lamellipodia formation during early steps of cell spreading. This seemed to be independent of RhoA activation, but dependent of Rac-1 inhibition by MAG. Laminin overrode MAG activity on actin and prevented MAG inhibition NGF-induced Rac1 activation. In conclusion, we evidenced antagonistic signaling between MAG receptors and beta1 integrins, in which Rac-1 may have a central function.

Animals↗

PubMed2000

Distinct structural forms of type I collagen modulate cell cycle regulatory proteins in mesangial cells.

BACKGROUND: Extracellular matrix molecules profoundly regulate cell behavior, including proliferation. In glomerulonephritis, type I collagen accumulates in the mesangium and is constantly structurally modified and degraded during the course of the disease. METHODS: We studied how two structurally distinct forms of type I collagen, monomer versus polymerized fibrils, affect cell proliferation, mitogen-activated protein kinase (MAPK) activation, and expression of G1-phase regulatory proteins in cultured rat mesangial cells (MCs). To analyze the possible involvement of collagen-binding integrins in type I collagen-derived growth signals further, distribution patterns of integrin chains were examined by immunocytochemistry. RESULTS: Polymerized type I collagen completely prevented the increase of DNA synthesis and cell replication induced by 5% fetal calf serum (FCS) or 25 ng/mL platelet-derived growth factor (PDGF) in MCs on monomer type I collagen. Protein expression of cyclins D1 and E was markedly down-regulated in MCs plated on polymerized type I collagen for eight hours in 5% FCS, as compared with MCs on monomer type I collagen. Incubation with 5% FCS reduced expression of the cdk-inhibitor protein p27Kip1 on monomer but not on polymerized type I collagen. Moreover, polymerized type I collagen markedly reduced cyclin E-associated kinase activity in the presence of 5% FCS. Polymerized type I collagen diminished the PDGF-induced phosphorylation and nuclear translocation of p42/p44 MAPK, but did not affect phosphorylation of PDGF beta-receptors. In MCs plated on monomer type I collagen, alpha1, alpha2, and beta1 integrin chains were recruited into focal contacts. However, on polymerized type I collagen, alpha2 and beta1, but not alpha1, integrin chains were condensed into focal contacts. CONCLUSIONS: The growth-inhibitory effect of polymerized type I collagen is characterized by rapid changes of expression and/or activation of MAPK and G1-phase regulators and could result from the lack of alpha1beta1 integrin signaling in MCs on polymerized type I collagen. Conceivably, deposition of polymerized type I collagen might reflect a reparative response to control MC replication in glomerular inflammation.

Animals↗

PubMed2003

Beta1 integrins are distributed in adhesion structures with fibronectin and caveolin and in coated pits.

Integrins are found in adhesion structures, which link the extracellular matrix to cytoskeletal proteins. Here, we attempt to further define the distribution of beta1 integrins in the context of their association with matrix proteins and other cell surface molecules relevant to the endocytic process. We find that beta1 integrins colocalize with fibronectin in fibrillar adhesion structures. A fraction of caveolin is also organized along these adhesion structures. The extracellular matrix protein laminin is not concentrated in these structures. The alpha4beta1 integrin exhibits a distinct distribution from other beta1 integrins after cells have adhered for 1 h to extracellular matrix proteins but is localized in adhesion structures after 24 h of adhesion. There are differences between the fibronectin receptors: alpha5beta1 integrins colocalize with adaptor protein-2 in coated pits, while alpha4beta1 integrins do not. This parallels our earlier observation that of the two laminin receptors, alpha1beta1 and alpha6beta1, only alpha1beta1 integrins colocalize with adaptor protein-2 in coated pits. Calcium chelation or inhibition of mitogen-activated protein kinase kinase, protein kinase C, or src did not affect localization of alpha1beta1 and alpha5beta1 integrins in coated pits. Likewise, the integrity of coated-pit structures or adhesion structures is not required for integrin and adaptor protein-2 colocalization. This suggests a robust and possibly constitutive interaction between these integrins and coated pits.

Adaptor Protein Complex 2↗

PubMed2000

Elevated matrix metalloprotease and angiostatin levels in integrin alpha 1 knockout mice cause reduced tumor vascularization.

Integrin alpha1beta1 is a collagen receptor abundantly expressed on microvascular endothelial cells. As well as being the only collagen receptor able to activate the Ras/Shc/mitogen-activated protein kinase pathway promoting fibroblast cell proliferation, it also acts to inhibit collagen and metalloproteinase (MMP) synthesis. We have observed that in integrin alpha1-null mice synthesis of MMP7 and MMP9 was markedly increased compared with that of their wild-type counterparts. As MMP7 and MMP9 have been shown to generate angiostatin from circulating plasminogen, and angiostatin acts as a potent inhibitor of endothelial cell proliferation, we determined whether tumor vascularization was altered in the alpha1-null mice. Tumors implanted into alpha1-null mice showed markedly decreased vascularization, with a reduction in capillary number and size, which was accompanied by an increase in plasma levels of angiostatin due to the action of MMP7 and MMP9 on circulating plasminogen. In vitro analysis of alpha1-null endothelial cells revealed a marked reduction of their proliferation on both integrin alpha1-dependent (collagenous) and independent (noncollagenous) substrata. This reduction was prevented by culturing alpha1-null cells with plasma derived from plasminogen-null animals, thus omitting the source from which to generate angiostatin. Plasma from tumor-bearing alpha1-null animals uniquely inhibited endothelial cell growth, and this inhibition was relieved by the coaddition of either MMP inhibitors, or antibody to angiostatin. Integrin alpha1-deficient mice thus provide a genetically characterized model for enhanced angiostatin production and serve to reveal an unwanted potential side effect of MMP inhibition, increased tumor angiogenesis.

Angiostatins↗

PubMed2006

Matrilins mediate weak cell attachment without promoting focal adhesion formation.

The matrilins form a family of non-collagenous adaptor proteins in the extracellular matrix. The extracellular ligand interactions of matrilins have been studied in some detail, while the potential interplay between matrilins and cells has been largely neglected. Except for matrilin-4, all matrilins mediate cell attachment, but only for matrilin-1 and -3 the binding is clearly dose dependent and seen already at moderate coating concentrations. Even so, much higher concentrations of matrilin-1 or -3 than of fibronectin are required for cell attachment to reach plateau values. Integrins contribute to the matrilin-mediated cell attachment, but the binding does not lead to formation of focal contacts and reorganisation of the actin cytoskeleton. Cells deficient in beta1 integrins are able to adhere, although weaker, and matrilins do not bind the soluble integrin alpha1beta1 and alpha2beta1 ectodomains. Cell surface proteoglycans may promote the attachment, as cells deficient in glycosaminoglycan biosynthesis adhere less well to matrilin-3. Even so, exogenous glycosaminoglycans are not able to compete for the attachment of HaCaT cells to matrilins.

Animals↗

PubMed1996

Characterization of the functional progesterone receptor in an endometrial adenocarcinoma cell line (Ishikawa): progesterone-induced expression of the alpha1 integrin.

Endometrial progesterone receptors (PR) are regulated by both estrogen (E2) and progesterone (P) and mediate the expression of specific endometrial proteins. Ishikawa cells are a well-differentiated human endometrial adenocarcinoma cell line, with both estrogen receptors (ER) and PR, regulated in a manner similar to that of normal endometrium. Immunohistochemical and biochemical analyses demonstrate that the concentration of PR is increased by E2 priming and decreased by subsequent treatment with P. Scatchard plot analysis showed a K(d) of 1 nM. On the basis of biochemical analysis, PR concentrations reached approximately 1400 fmol/mg cytosol protein in cells after treatment with E2 (10(-8) M) for 4 days. Immunoprecipitation and Western blot studies revealed the presence of both the 116 kDa and 81 kDa proteins with multiple isoforms of the high molecular weight (MW) protein. Northern blot analysis demonstrated transcriptional control of PR by steroid treatment. These studies demonstrate the coordinate regulation of all PR mRNA species. The functionality of Ishikawa PR was demonstrated by the expression of alpha1beta1 integrin in response to E2 plus P, at the level of transcription and translation. This effect was blocked by the addition of the anti-progestin, RU-486. These studies reconfirm that the Ishikawa cell line is an excellent model for the study of hormonally regulated events in the human endometrial epithelium.

Adenocarcinoma↗

PubMed2005

Lebestatin, a disintegrin from Macrovipera venom, inhibits integrin-mediated cell adhesion, migration and angiogenesis.

Lebestatin, a new member of the lysine-threonine-serine (KTS)-disintegrin family, was purified to homogeneity from Tunisian snake (Macrovipera lebetina) venom. It is a single-chain polypeptide composed of 41 amino acids. The amino-acid sequence of lebestatin shows that it displays a pattern of cysteines similar to other short disintegrins, but contains the sequence KTS rather than RGD in its integrin-binding loop. Lebestatin presents a high homology with obtustatin and viperistatin. Lebestatin interacts specifically with the alpha1beta1 integrin. It was thus able to inhibit both adhesion and migration of PC12 and alpha1beta1 integrin-expressing CHO cells (CHO-alpha1) to type I and IV collagens. This disintegrin also affected adhesion and migration of endothelial cells and exhibited an anti-angiogenic effect in vivo when using the 8-day-old embryo chick chorioallantoic membrane model.

Allantois↗

PubMed2003

Collagen IV regulates Caco-2 migration and ERK activation via alpha1beta1- and alpha2beta1-integrin-dependent Src kinase activation.

Our previous work indicates intestinal epithelial cell ERK activation by collagen IV, a major component of the intestinal epithelial basement membrane, requires focal adhesion kinase (FAK) and suggests FAK and ERK may have important roles in regulating intestinal epithelial cell migration. We therefore sought to identify FAK downstream targets regulating intestinal epithelial cell spreading, migration, and ERK activation on collagen IV and the integrins involved. Both dominant-negative Src and Src inhibitor PP2 strongly inhibited collagen IV ERK activation in Caco-2 intestinal epithelial cells. Collagen IV stimulated Grb2 binding site FAK Y925 phosphorylation, which was inhibited by PP2 and required FAK Y397 autophosphorylation. Additionally, FAK Y925F expression blocked collagen IV ERK activation. alpha(1)beta(1)- Or alpha(2)beta(1)-integrin blockade with alpha(1)- or alpha(2)-integrin subunit antibodies indicated that either integrin can mediate adhesion, cell spreading, and FAK, Src, and ERK activation on collagen IV. Both dominant-negative Src and PP2 inhibited Caco-2 spreading on collagen IV. PP2 inhibited p130(Cas) tyrosine phosphorylation, but dominant-negative p130(Cas) did not inhibit cell spreading. PP2 inhibited Caco-2 migration on collagen IV much more strongly than the mitogen-activated protein kinase kinase inhibitor PD-98059, which completely inhibited collagen IV ERK activation. These results suggest a pathway for collagen IV ERK activation requiring Src phosphorylation of FAK Y925 not previously described for this matrix protein and suggest either alpha(1)beta(1)- or alpha(2)beta(1)-integrins can regulate Caco-2 spreading and ERK activation on collagen IV via Src. Additionally, these results suggest Src regulates Caco-2 migration on collagen IV primarily through ERK-independent pathways.

Antibodies, Blocking↗

PubMed1997

The laminin alpha2-chain short arm mediates cell adhesion through both the alpha1beta1 and alpha2beta1 integrins.

Laminin-2, a heterotrimer composed of alpha2, beta1, and gamma1 subunits, is the primary laminin isoform found in muscle and peripheral nerve and is essential for the development and stability of basement membranes in these tissues. Expression of a domain VI-truncated laminin alpha2-chain results in muscle degeneration and peripheral nerve dysmyelination in the dy2J dystrophic mouse. We have expressed amino-terminal domains VI through IVb of the laminin alpha2-chain, as well as its laminin-1 alpha1-chain counterpart, to identify candidate cell-interactive functions of this critical region. Using integrin-specific antibodies, recognition sites for the alpha1beta1 and alpha2beta1 integrins were identified in the short arms of both laminin alpha1- and alpha2-chain isoforms. Comparisons with a beta-alpha chimeric short arm protein possessing beta1-chain domain VI further localized these activities to alpha-chain domain VI. In addition, we found that the laminin alpha2-chain short arm supported neurite outgrowth independent of other laminin-2 subunits. A heparin/heparan sulfate binding activity was also localized to this region of the laminin alpha2 subunit. These data provide the first evidence that domain VI of the laminin alpha2-chain mediates interactions with cell surface receptors and suggest that these integrin and heparin binding sites, alone or in concert, may play an important role in muscle and peripheral nerve function.

Animals↗

PubMed2000

Integrin expression by primary and immortalized human chondrocytes: evidence of a differential role for alpha1beta1 and alpha2beta1 integrins in mediating chondrocyte adhesion to types II and VI collagen.

OBJECTIVE: Chondrocytes have been shown to express beta1-containing integrins both in vitro and in situ, but their role in regulating chondrocyte function is poorly understood. The objective of this study was to determine how the relative expression of different integrins may be modulated in relation to the differentiated state and proliferative capacity of the chondrocyte. DESIGN: Integrin expression by four different cell lines of human chondrocytes immortalized with Simian virus 40 large T-antigen (SV40-TAg) was studied and compared to primary chondrocytes. Differences in alpha1 and alpha2 integrin subunit expression were utilized to further study the role of these integrins in mediating adhesion to types II and VI collagen. RESULTS: The overall cell-surface levels of beta1-containing integrins were higher on all four immortalized cell lines which expressed over 10-fold higher levels of alpha2 and alpha3 integrin subunits compared to primary cells. However, primary cells expressed higher levels of the alpha1 integrin subunit which was not expressed by T/C28a4 cells and expressed at variable and lower levels in the other lines. Levels of the alpha3 integrin subunit were significantly greater on the highly proliferative juvenile costal chondrocyte lines (T/C-28a4, C-2812, and C-20a4) compared to primary articular chondrocytes and tsT/AC-62 cells which were derived from adult articular chondrocytes. Expression of alpha5 was similar among primary cells and cell lines except on C-20/A4 cells which had an average of over 4-fold higher levels. None of the primary or immortalized chondrocytes tested expressed significant levels of alpha4. Cell adhesion assays revealed that both alpha1beta1 and alpha2beta1 could serve as chondrocyte adhesion receptors for types II and VI collagen. In cell lines expressing both integrins, alpha1beta1 was the preferential receptor for type VI collagen while alpha2beta1 was the preferential receptor for type II collagen. Rather than inhibiting adhesion, incubation with the alpha3 blocking antibody P1B5 increased adhesion of C-28/12 cells to both fibronectin and type II collagen by 67% and 100% respectively. CONCLUSIONS: Immortalization with SV40-TAg results in altered integrin expression by chondrocytes. Changes in the relative levels of alpha1, alpha2, and alpha3 subunits may significantly alter the manner in which chondrocytes interact with types II and VI collagen in the extracellular matrix.

Adult↗

PubMed2005

Collagen-binding integrins as pharmaceutical targets.

In recent years, our understanding of the molecular interaction of collagens with their cognate integrin receptors has remarkably improved. Structural elucidations of both the integrin and the collagenous triple helix have contributed to this achievement. The structures of an entire integrin ectodomain and of an A-domain, which is unique to the integrin alpha subunits of collagen-binding and leukocyte integrins, have been resolved crystallographically. Furthermore, a complex of such an integrin alpha subunit A-domain with its collagenous binding partner has revealed their interaction on the molecular level and gave first evidence in the conformational alterations which may convey the signal of ligand occupancy through the integrin into the cells. In parallel, the tissue distribution and biological functions of collagen-binding integrins have been characterised. Nowadays, the contribution of distinct integrins to different physiological and pathological processes is known. Among the best studied examples is the collagen-induced platelet activation and aggregation, in which alpha2beta1 integrin is involved. Together with alpha1beta1 integrin, it also plays a role in inflammatory processes. To manipulate processes which are mediated by collagen-binding integrins, compounds are developed which mimic the collagen ligand. Not only the structural information of the integrin:collagen-interaction but also improvements in the chemical synthesis of a collagenous triple helix facilitate the development of agonists and antagonists of collagen-binding integrins. Furthermore, another impact in this search comes from the discovery of high-affinity inhibitors from venoms, which lack a collagenous triple-helix.

Animals↗

PubMed2001

Analysis of cell-free human alpha1 integrin with a monoclonal antibody to the I-domain: detection in ocular fluid and function as an adhesion substrate.

The alpha1 beta1 integrin, an inserted (1) domain containing collagen receptor, is expressed in the cell surface membrane of normal and malignant cells, and may play a role in their migration through tissues or in metastatic spread. Here we report that a functional anti-human alpha1beta1 integrin monoclonal antibody (mAb) (1B3.1) directly and specifically binds plastic bound recombinant human alpha1 I-domain protein containing the collagen binding site. Detection was diminished by acidification of the I-domain protein but was enhanced by increasing concentrations of Mg2+ cation. Furthermore, we detected binding of the mAb to proteins from the ocular fluids of 6 patients, with the highest concentration, corresponding to 22.1 ng/ml of I-domain, found in a sample from the eye of a patient with metastatic lung adenocarcinoma. Interestingly, we found that both SKNSH neuroblastoma cells and virally transformed human T cells adhered specifically to plastic wells coated with either immobilized collagen IV or alpha1 I-domain. MAb I B3.1 inhibited adhesion to collagen IV but not to immobilized I-domain. These results suggest a novel function for cell free alpha1 I-domain as a substrate for cellular adhesion, which may have relevance in tumor spread in vivo.

Adenocarcinoma↗

PubMed2003

A monoclonal antibody to alpha1beta1 blocks antigen-induced airway responses in sheep.

The integrin alpha1beta1 (very late antigen-1; CD49a/CD29) is a major adhesion receptor for collagen I, IV, and VI, and its induced expression on activated monocytes and lymphocytes plays a central role in their retention and activation at inflammatory sites in autoimmune pathologies. However, the role of alpha1beta1 in allergic settings has not been explored. In this study, we show that a single 45-mg dose of aerosolized monoclonal antibody AQC2 to the alpha1 chain of human and sheep very late antigen-1, given 30 minutes before challenge, blocks both the allergen-induced late response and the associated airway hyperresponsiveness, functional indicators of allergen-induced inflammation, in sheep. AQC2 does not affect the early response. Consistent with these effects, AQC2 tended to reduce the cell response associated with local antigen instillation. An isotype-matched control antibody had no protective effects. Two humanized versions of AQC2, a wild-type IgG1 and an aglycosyl form of the same monoclonal antibody, which has reduced Fc receptor-mediated effector functions, are equally effective in blocking the antigen-induced late response and airway hyperresponsiveness in the sheep model. These data suggest that mononuclear leukocyte adhesion-dependent pathologies contribute to allergic lung disease and provide proof-of-concept that antagonists of alpha1 integrins may be useful in preventing these events.

Administration, Inhalation↗

PubMed1998

Alpha2beta1 integrin recognition of the carboxyl-terminal propeptide of type I procollagen: integrin recognition and feed-back regulation of matrix biosynthesis are mediated by distinct sequences.

It has recently been established that the carboxyl-terminal propeptide of type I collagen exert a feedback regulatory effect on extracellular matrix biosynthesis and that the propeptide bind to the alpha2beta1 integrin. This raises the intriguing hypothesis that the regulatory propeptide sequences exert their effects as a consequence of binding to the integrin. We show that recombinant alpha1(I) collagen chain C-terminal propeptide contains a binding site for the intact alpha2beta1 integrin and for a recombinant alpha2 integrin I domain, but not for the alpha1beta1 integrin, a structurally and functionally related collagen/laminin receptor. Additional studies employing a series of recombinant N-terminal and C-terminal deletion mutants, internal fragments of the propeptide, synthetic peptides, recombinant alpha2 integrin I domain and inhibitory monoclonal antibodies established that the previously identified sequences within the alpha1(I) C-terminal propeptide that mediate regulation of matrix biosynthesis are neither necessary nor sufficient for alpha2beta1 integrin binding. In contrast, the integrin recognition site is composed of a conformationally complex determinant located within a structurally distinct 115 amino acid region of the propeptide.

Animals↗