Structural Insight into the Function of Myelin Basic Protein as a Ligand for Integrin αMβ2

Stapulionis, Romualdas; Oliveira, Cristiano L. P.; Gjelstrup, Mikkel Carstensen; Pedersen, Jan Skov; Hokland, Marianne; Hoffmann, Søren Vrønning; Poulsen, Knud; Jacobsen, Christian; Vorup-Jensen, Thomas

doi:10.4049/jimmunol.180.6.3946

Cited by 67 publications

(70 citation statements)

References 60 publications

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“…Furthermore, the demonstration that in MHC class II-deficient mice, GA induces type II monocyte differentiation favoring the production of antiinflammatory cytokines, strongly indicates that GA may affect monocyte function in the absence of MHC class II molecules (47). In addition to MHC class II, GA has been shown to interact with Mac-1 (CD11b/CD18 integrin) (48). Ligation of β2-integrins by either CD23 or antibodies induces the production of IL-1β in human monocytes that depends on the early (2-5 min) phosphorylation of ERK1/2 (49).…”

Section: Discussionmentioning

confidence: 99%

Glatiramer acetate triggers PI3Kδ/Akt and MEK/ERK pathways to induce IL-1 receptor antagonist in human monocytes

Carpintero

Brandt

Gruaz

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Glatiramer acetate (GA), an immunomodulator used in multiple sclerosis (MS) therapy, induces the production of secreted IL-1 receptor antagonist (sIL-1Ra), a natural inhibitor of IL-1β, in human monocytes, and in turn enhances sIL-1Ra circulating levels in MS patients. GA is a mixture of peptides with random Glu, Lys, Ala, and Tyr sequences of high polarity and hydrophilic nature that is unlikely to cross the blood–brain barrier. In contrast, sIL-1Ra crosses the blood–brain barrier and, in turn, may mediate GA anti-inflammatory activities within the CNS by counteracting IL-1β activities. Here we identify intracellular signaling pathways induced by GA that control sIL-1Ra expression in human monocytes. By using kinase knockdown and specific inhibitors, we demonstrate that GA induces sIL-1Ra production via the activation of PI3Kδ, Akt, MEK1/2, and ERK1/2, demonstrating that both PI3Kδ/Akt and MEK/ERK pathways rule sIL-1Ra expression in human monocytes. The pathways act in parallel upstream glycogen synthase kinase-3α/β (GSK3α/β), the knockdown of which enhances sIL-1Ra production. Together, our findings demonstrate the existence of signal transduction triggered by GA, further highlighting the mechanisms of action of this drug in MS.

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Section: Discussionmentioning

confidence: 99%

Glatiramer acetate triggers PI3Kδ/Akt and MEK/ERK pathways to induce IL-1 receptor antagonist in human monocytes

Carpintero

Brandt

Gruaz

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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“…The data were analyzed by a recently developed model (30), which calculates the minimal distribution in kinetic parameters (i.e., k a and k d ), required to account for the experimentally observed kinetics by assuming that the sensorgrams are a sum of multiple pseudo first-order reactions. The model has been applied in several other experimental analyses of heterogenous interactions (31,32,54,55 …”

Section: Binding Of Mbl 3 Oligomers Analyzed By a Model With Continuomentioning

confidence: 99%

“…As demonstrated by Svitel et al (30), heterogeneity in ligand binding can be resolved into an ensemble of 1:1 pseudo first-order reactions with a continuous distribution of binding constants. This methodology was used in a number of studies in which the surface-immobilized ligands presented a heterogeneous composition (31)(32)(33)(34)(35). As pointed out by Svitel et al (30), the same methodology also applies for situations in which the analyte is a composition of molecules with heterogeneous ligand-binding properties (e.g., as potentially would be the case for analyzing the avidity of a mixture of MBL 3 oligomers).…”

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confidence: 99%

The Role of Nanometer-Scaled Ligand Patterns in Polyvalent Binding by Large Mannan-Binding Lectin Oligomers

Gjelstrup

Kaspersen

Behrens

et al. 2012

The Journal of Immunology

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Mannan-binding lectin (MBL) is an important protein of the innate immune system and protects the body against infection through opsonization and activation of the complement system on surfaces with an appropriate presentation of carbohydrate ligands. The quaternary structure of human MBL is built from oligomerization of structural units into polydisperse complexes typically with three to eight structural units, each containing three lectin domains. Insight into the connection between the structure and ligand-binding properties of these oligomers has been lacking. In this article, we present an analysis of the binding to neoglycoprotein-coated surfaces by size-fractionated human MBL oligomers studied with small-angle x-ray scattering and surface plasmon resonance spectroscopy. The MBL oligomers bound to these surfaces mainly in two modes, with dissociation constants in the micro to nanomolar order. The binding kinetics were markedly influenced by both the density of ligands and the number of ligand-binding domains in the oligomers. These findings demonstrated that the MBL-binding kinetics are critically dependent on structural characteristics on the nanometer scale, both with regard to the dimensions of the oligomer, as well as the ligand presentation on surfaces. Therefore, our work suggested that the surface binding of MBL involves recognition of patterns with dimensions on the order of 10–20 nm. The recent understanding that the surfaces of many microbes are organized with structural features on the nanometer scale suggests that these properties of MBL ligand recognition potentially constitute an important part of the pattern-recognition ability of these polyvalent oligomers.

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“…Samples of 400 ml culture medium, including cells were harvested after 24 h, 48 h, 72 h, and 120 h of incubation at 37˚C in a humidified atmosphere with 5% (v/v) CO 2 , followed by separation of cells and medium by centrifugation. The cells were analyzed by flow cytometry (35). MNCs were stained for CD45 and CD14 expression as well as viability with 7-aminoactinomycin D (7-AAD; Via-Probe; catalog no.…”

Section: Experimental Induction Of Cd18 Sheddingmentioning

confidence: 99%

“…Peripheral mononuclear cells (MNCs) were harvested from HV peripheral blood as described elsewhere (35) and used either immediately or following storage at -134˚C in 70% (v/v) RPMI 1640, 20% (v/v) FCS, and 10% (v/v) DMSO. For studies on the time course of CD18 shedding freshly isolated granulocytes were separated from MNCs and erythrocytes by centrifugation on a Histopaque 1077 and 1019 gradient (Sigma-Aldrich) as described (36).…”

Section: Experimental Induction Of Cd18 Sheddingmentioning

confidence: 99%

Shedding of Large Functionally Active CD11/CD18 Integrin Complexes from Leukocyte Membranes during Synovial Inflammation Distinguishes Three Types of Arthritis through Differential Epitope Exposure

Gjelstrup

Boesen

Kragstrup

et al. 2010

The Journal of Immunology

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CD18 integrins are adhesion molecules expressed on the cell surface of leukocytes and play a central role in the molecular mechanisms supporting leukocyte migration to zones of inflammation. Recently, it was discovered that CD11a/CD18 is shed from the leukocyte surface in models of inflammation. In this study, we show that shedding of human CD11/CD18 complexes is a part of synovial inflammation in rheumatoid arthritis and spondyloarthritis but not in osteoarthritis. In vivo and in vitro data suggest that the shedding is driven by TNF-α, which links the process to central events in the inflammatory response. The shed complexes contain multiple heterodimers of CD11/CD18, are variable in size, and differ according to the type of synovial inflammation. Furthermore, the differential structures determine the avidity of binding of the complexes to the ICAM-1. With the estimated concentrations of CD11/CD18 in plasma and synovial fluid a significant coverage of binding sites in ICAM-1 for CD18 integrins is expected. Based on cell adhesion experiments in vitro, we hypothesize that the large soluble complexes of CD11/CD18 act in vivo to buffer leukocyte adhesion by competing with the membrane-bound receptors for ICAM-1 binding sites. As reported here for synovial inflammation changes in the concentration or structure of these complexes should be considered as likely contributors to disease activity.

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Structural Insight into the Function of Myelin Basic Protein as a Ligand for Integrin αMβ2

Cited by 67 publications

References 60 publications

Glatiramer acetate triggers PI3Kδ/Akt and MEK/ERK pathways to induce IL-1 receptor antagonist in human monocytes

Glatiramer acetate triggers PI3Kδ/Akt and MEK/ERK pathways to induce IL-1 receptor antagonist in human monocytes

The Role of Nanometer-Scaled Ligand Patterns in Polyvalent Binding by Large Mannan-Binding Lectin Oligomers

Shedding of Large Functionally Active CD11/CD18 Integrin Complexes from Leukocyte Membranes during Synovial Inflammation Distinguishes Three Types of Arthritis through Differential Epitope Exposure

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