INVOLVEMENT OF Α-2-Macroglobulin RECEPTOR IN CLEARANCE OF INTERLEUKIN 8–α-2-Macroglobulin COMPLEXES BY HUMAN ALVEOLAR MACROPHAGES

Kurdowska, Anna; Alden, Susanne M; Noble, James M.; Stevens, Michael D.; Carr, Ferdicia K.

doi:10.1006/cyto.1999.0640

Cited by 17 publications

(25 citation statements)

References 43 publications

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“…All four are secreted glycoproteins widely distributed in most physiological fluids, including plasma and CSF (Barrett 1981;Baltz et al, 1982;Bowman and Kurosky 1982;. Moreover, all bind to a broad range of ligands (Barrett 1981;Capiau et al, 1986;Katnik et al, 1987;Aruga et al, 1993;Katnik et al, 1993;Zahedi 1996;Ashton et al, 1997;Langlois et al, 1997;Zahedi 1997;Kurdowska et al, 2000;Wilson and Easterbrook-Smith 2000;Kimura et al, 2001;Sen and Heegaard 2002) and have been found associated with clinical amyloid deposits in vivo (Table (1)) (Powers et al, 1981;Baltz et al, 1982;Van Gool et al, 1993;McHattie and Edington 1999;Calero et al, 2000). In addition all have been shown to mediate receptormediated endocytosis of ligands (see below).…”

Section: Extracellular Chaperonesmentioning

confidence: 99%

Extracellular Chaperones and Amyloids

Wilson¹,

Yerbury²,

Poon³

2008

Heat Shock Proteins and the Brain: Implications for Neurodegenerative Diseases and Neuroprotection

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The pathology of more than 40 human degenerative diseases is associated with fibrillar proteinaceous deposits called amyloid. Collectively referred to as protein deposition diseases, many of these affect the brain and the central nervous system. In many cases the amyloid deposits are extracellular and are found associated with newly identified abundant extracellular chaperones (ECs). Evidence is discussed which suggests an important regulatory role for ECs in amyloid formation and disposal in vivo. This is emerging as an exciting field. A model is presented in which it is proposed that, under normal conditions, ECs stabilize extracellular misfolded proteins by binding to them, and then guide them to specific receptors for uptake and subsequent degradation. In this scenario, EC receptors are a critical part of a quality control system which protects the brain against dangerously hydrophobic proteins/peptides. However, it also appears possible that in the presence of a high molar excess of misfolded protein, such as might occur during disease, the limited amounts of ECs available may actually exacerabate pathology. Further advances in understanding of the mechanisms that control extracellular protein folding are likely to identify new strategies for effective disease therapies. ABSTRACTThe pathology of more than 40 human degenerative diseases is associated with fibrillar proteinaceous deposits called amyloid. Collectively referred to as protein deposition diseases, many of these affect the brain and the central nervous system. In many cases the amyloid deposits are extracellular and are found associated with newly identified abundant extracellular chaperones (ECs). Evidence is discussed which suggests an important regulatory role for ECs in amyloid formation and disposal in vivo. This is emerging as an exciting field. A model is presented in which it is proposed that, under normal conditions, ECs stabilize extracellular misfolded proteins by binding to them, and then guide them to specific receptors for uptake and subsequent degradation. In this scenario, EC receptors are a critical part of a quality control system which protects the brain against dangerously hydrophobic proteins/peptides. However, it also appears possible that in the presence of a high molar excess of misfolded protein, such as might occur during disease, the limited amounts of ECs available may actually exacebate pathology. Further advances in understanding of the mechanisms that control extracellular protein folding are likely to identify new strategies for effective disease therapies.

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Section: Extracellular Chaperonesmentioning

confidence: 99%

Extracellular Chaperones and Amyloids

Wilson¹,

Yerbury²,

Poon³

2008

Heat Shock Proteins and the Brain: Implications for Neurodegenerative Diseases and Neuroprotection

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“…rhIL-8-"fast" human a 2 M complexes bound to human neutrophils with comparable affinity to rhIL-8 alone, and had a neutrophil activating ability similar to that of "free" rhIL-8 [13]. In addition, complexes between rhIL-8 and "fast" human a 2 M were cleared by human alveolar macrophages via a 2 M receptors [14]. Furthermore, studies from our laboratory demonstrated that a significant portion (up to 60 %) of IL-8 in lung fluids from patients with ARDS is associated with a 2 M [13].…”

Section: Introductionmentioning

confidence: 99%

Specific binding of IL-8 to rabbit α -macroglobulin modulates IL-8 function in the lung

Kurdowska

Fujisawa

Peterson

et al. 2000

Inflammation Research

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“…The conformational change that occurs with α 2 M activation also exposes binding sites for nonprotease ligands, including PDGF (Huang et al, 1984), FGF (Mathew et al, 2003), TGFβ1 (Huang et al, 1988;Stouffer et al, 1993;Feige et al, 1996;Arandjelovic et al, 2003), Activin A (Niemuller et al, 1995;Mather, 1996;Phillips, 2000), NGF (Ronne et al, 1979), TNF (James et al, 1992) and multiple Interleukins (Borth and Luger, 1989;Borth et al, 1990;Garber et al, 2000;Kurdowska et al, 2000). In complex with these ligands, α 2 M can serve either as a carrier that stabilizes ligand in circulation, a clearance factor for ligand degradation, or as a targeting factor for cellular uptake and subcellular localization of ligand.…”

Section: Resultsmentioning

confidence: 99%

“…Binding of protease to native α 2 M results in cleavage and activation of α 2 M, causing a conformational change that entraps protease and exposes binding sites for the α 2 M receptor. The α 2 M-protease complex binds to low density lipoprotein receptor-related protein (LRP), the major cell surface receptor for α 2 M, and the receptor bound complex is internalized by endocytosis, and targeted for lysosomal degradation (reviewed in Borth, 1992).* Author for correspondence Email:kesslerd@mail.med.upenn.edu, Tel: 215-898-1478, Fax: 215-573-7601 The conformational change that occurs with α 2 M activation also exposes binding sites for nonprotease ligands, including PDGF (Huang et al, 1984), FGF (Mathew et al, 2003), TGFβ1 (Huang et al, 1988;Stouffer et al, 1993;Feige et al, 1996;Arandjelovic et al, 2003), Activin A (Niemuller et al, 1995;Mather, 1996;Phillips, 2000), NGF (Ronne et al, 1979), TNF (James et al, 1992) and multiple Interleukins (Borth and Luger, 1989;Borth et al, 1990;Garber et al, 2000;Kurdowska et al, 2000). In complex with these ligands, α 2 M can serve either as a carrier that stabilizes ligand in circulation, a clearance factor for ligand degradation, or as a targeting factor for cellular uptake and subcellular localization of ligand.…”

mentioning

confidence: 99%

Expression of Panza, an α2-macroglobulin, in a restricted dorsal domain of the primitive gut in Xenopus laevis

Pineda-Salgado

Craig

Blank

et al. 2005

Gene Expression Patterns

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Abstractα2-macroglobulin is a major serum protein with diverse functions, including inhibition of protease activity and binding of growth factors, cytokines, and disease factors. We have cloned and characterized Panza, a new Xenopus laevis α2-macroglobulin. Panza has 56-60% amino acid similarity with previously identified Xenopus, mouse, rat and human α2-macroglobulins, indicating that Panza is a new member of the α2-macroglobulin family. Panza mRNA is first detected at the beginning of neurulation in the dorsal endoderm lining the primitive gut (archenteron roof). At the completion of neurulation and continuing through the late tadpole stage, Panza is restricted to a dorsal domain of the gut endoderm adjacent to the notochord and extending along the entire anteriorposterior axis. With outgrowth of the tailbud, Panza expression persists in the chordaneural hinge at the posterior end of the differentiating notochord and extends into the floor plate of the posterior neural tube. As gut coiling commences, Panza expression is initiated in the liver, and the dorsal domain of Panza expression becomes limited to the midgut and hindgut. With further gut coiling, strong Panza expression persists in the liver, but is lost from other regions of the gut. The expression of Panza in endodermal cells adjacent to the notochord points to a potential role for Panza in signal modulation and/or morphogenesis of the primitive gut. KeywordsXenopus laevis; α2-macroglobulin; endoderm; gut; digestive tract; liver Results and Discussionα2-macroglobulin (α 2 M) is an abundant plasma protein of vertebrates and arthropods that has a remarkable capacity to bind numerous and diverse ligands. α 2 M was first identified as a "panprotease inhibitor" capable of binding nearly all extracellular proteases, leading to clearance and degradation of α 2 M-protease complexes. Binding of protease to native α 2 M results in cleavage and activation of α 2 M, causing a conformational change that entraps protease and exposes binding sites for the α 2 M receptor. The α 2 M-protease complex binds to low density lipoprotein receptor-related protein (LRP), the major cell surface receptor for α 2 M, and the receptor bound complex is internalized by endocytosis, and targeted for lysosomal degradation (reviewed in Borth, 1992).* Author for correspondence Email:kesslerd@mail.med.upenn.edu, Tel: 215-898-1478, Fax: 215-573-7601 The conformational change that occurs with α 2 M activation also exposes binding sites for nonprotease ligands, including PDGF (Huang et al., 1984), FGF (Mathew et al., 2003), TGFβ1 (Huang et al., 1988;Stouffer et al., 1993;Feige et al., 1996;Arandjelovic et al., 2003), Activin A (Niemuller et al., 1995;Mather, 1996;Phillips, 2000), NGF (Ronne et al., 1979), TNF (James et al., 1992) and multiple Interleukins (Borth and Luger, 1989;Borth et al., 1990;Garber et al., 2000;Kurdowska et al., 2000). In complex with these ligands, α 2 M can serve either as a carrier that stabilizes ligand in circulation, a clearance factor for ligand degradation, or ...

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INVOLVEMENT OF Α-2-Macroglobulin RECEPTOR IN CLEARANCE OF INTERLEUKIN 8–α-2-Macroglobulin COMPLEXES BY HUMAN ALVEOLAR MACROPHAGES

Cited by 17 publications

References 43 publications

Extracellular Chaperones and Amyloids

Extracellular Chaperones and Amyloids

Specific binding of IL-8 to rabbit α -macroglobulin modulates IL-8 function in the lung

Expression of Panza, an α2-macroglobulin, in a restricted dorsal domain of the primitive gut in Xenopus laevis

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