Induction of ?1-antitrypsin synthesis in human articular chondrocytes by interleukin-6-type cytokines: Evidence for a local acute-phase response in the joint

Fischer, Dagmar‐Christiane; Siebertz, Barbara; Leur, Eddy Van de; Schiwy-Bochat, Karl-Heinz; Graeve, Lutz; Heinrich, P.C.; Haubeck, H.-D.

doi:10.1002/1529-0131(199909)42:9<1936::aid-anr20>3.0.co;2-k

Cited by 21 publications

(18 citation statements)

References 58 publications

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“…For example, in lung-derived epithelial cells (HTB 58), in lung adenocarcinoma cells (HTB 55) and in human alveolar epithelial cells neither IL-1b nor IL-6 had any influence on a1-PI secretion [3,31,32]. In contrast, a1-PI release was found to be enhanced by those cytokines in hepatocytes, cornea cells, articular chondrocytes and monocytes/macrophages [4,5,33,34]. Taken together, these data could imply that the absence of the effect of IL-1b and IL-6 on a1-PI release might be specific for alveolar and intestinal epithelial cells.…”

Section: Discussionmentioning

confidence: 98%

“…a1-PI is primarily a liver-derived serum protein with a molecular weight between 52 and 55 kDa. Recent studies showed that a1-PI is also synthesized outside the liver: by alveolar epithelial cells [3], monocytes [4], chondrocytes [5], human cornea [6] and, of importance for local control of inflammatory processes in the gut, in intestinal epithelial cells [7].…”

Section: Introductionmentioning

confidence: 99%

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Regulation ofα1-proteinase inhibitor release by proinflammatory cytokines in human intestinal epithelial cells

Faust

Raschke

Hormann

et al. 2002

Clinical and Experimental Immunology

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SUMMARYa1-Proteinase inhibitor (a1-PI) is the main serine proteinase inhibitor in human plasma. Apart from its synthesis in the liver, this anti-inflammatory protein is also synthesized by and excreted from human intestinal epithelial cells. Antiinflammatory actions of a1-PI are thought to be of relevance in the pathogenesis of inflammatory bowel disease. To investigate the role of macrophage-derived cytokines on a1-PI secretion from intestinal epithelial cells, we cultured Caco-2 cells until differentiation (14 days in culture) on permeable filter supports. Monolayers of differentiated Caco-2 cells were then co-cultured with human peritoneal macrophages, grown on plastic in the basolateral chamber. Under these conditions, a1-PI secretion from Caco-2 cells was enhanced by 45%, probably by a direct action of macrophage-derived cytokines on Caco-2 cells. To extend this observation further, we treated differentiated Caco-2 cells with macrophage-derived proinflammatory cytokines (IL-1b, IL-8, TNF-a), as well as with lymphocyte-derived cytokines IL-2, IL-6 and IFN-g. As early as after 24 h treatment, IL-2 and IL-8 induced a significant and dose-dependent increase of a-1-PI secretion into cell culture medium; this effect was completely reversed after immunoneutralization by the antibodies against IL-2 and IL-8 a1-PI secretion was only slightly decreased after treatment with IFN-g, while IL-1b, IL-6 and TNFa had no effect. a1-PI secretion correlated well with the expression of this protein in differentiated Caco-2 cells after cytokine treatment, as confirmed by Western blot. Our data imply that, in vitro, a1-PI secretion in enterocyte-like Caco-2 cells is up-regulated by IL-2 and IL-8. Our results suggest that both lymphocyte-and macrophage-derived cytokines regulate secretion of the anti-inflammatory protein a1-PI in intestinal epithelial cells.

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Section: Discussionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

Regulation ofα1-proteinase inhibitor release by proinflammatory cytokines in human intestinal epithelial cells

Faust

Raschke

Hormann

et al. 2002

Clinical and Experimental Immunology

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“…In human neutrophils, monocytes, alveolar macrophages and intestinal epithelial cells, AAT expression increases in response to inflammatory mediators such as lipopolysaccharide, TNFa, interleukin (IL)-1, IL-6, and the complex of AAT and neutrophil elastase. [16][17][18][19] Increasing evidence indicates that the anti-inflammatory properties of AAT may allow for it to serve as a therapeutic agent for altering the immune response. For example, AAT delivery can completely abolish acute inflammatory infiltration and connective tissue breakdown.…”

Section: Introductionmentioning

confidence: 99%

Recombinant adeno-associated virus-mediated alpha-1 antitrypsin gene therapy prevents type I diabetes in NOD mice

et al. 2004

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Type I diabetes results from an autoimmune destruction of the insulin-producing pancreatic b cells. Although the exact immunologic processes underlying this disease are unclear, increasing evidence suggests that immunosuppressive, immunoregulatory and anti-inflammatory agents can interrupt the progression of the disease. Alpha 1 antitrypsin (AAT) is a multifunctional serine proteinase inhibitor (serpin) that also displays a wide range of anti-inflammatory properties. To test the ability of AAT to modulate the development of type I diabetes, we performed a series of investigations involving recombinant adeno-associated virus vector (rAAV)-mediated gene delivery of human alpha-1 antitrypsin (hAAT) to nonobese diabetic (NOD) mice. Recombinant AAV-expressing hAAT (rAAV2-CB-AT) was administered intramuscularly to 4-week-old female NOD mice (1 Â 10 10 i.u./mouse). A single injection of this vector reduced the intensity of insulitis, the levels of insulin autoantibodies, and the frequency of overt type I diabetes (30% (3/10) at 32 weeks of age versus 70% (7/10) in controls). Transgene expression at the injection sites was confirmed by immunostaining. Interestingly, antibodies against hAAT were present in a majority of the vector-injected mice and circulating hAAT was undetectable when assessed 10 weeks postinjection. This study suggests a potential therapeutic role for AAT in preventing type I diabetes as well as the ability of AAV gene therapy-based approaches to ameliorate disease effectively.

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“…5). AAT may facilitate the survival of islet transplants in engrafted patients, because the inhibitor prevents inflammatory cytokine production, blocks immune cell infiltration and function, inhibits complement activation, and delays the development of diabetes in nonobese diabetic mice (5)(6)(7)(8)(9)(10)(11)(12).…”

mentioning

confidence: 99%

α1-Antitrypsin monotherapy prolongs islet allograft survival in mice

Lewis

Shapiro

Bowers

et al. 2005

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

167

203

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Islet transplantation for type 1 diabetic patients shows promising results with the use of nondiabetogenic immunosuppressive therapy. However, in addition to compromising the immune system of transplant recipients, long-term studies demonstrate that islet viability is impaired. Here, we demonstrate that, in the absence of immunosuppressive agents, monotherapy with clinical-grade human ␣1-antitrypsin (hAAT), the major serum serine-protease inhibitor, prolongs islet graft survival and normoglycemia in transplanted allogeneic diabetic mice, lasting until the development of anti-hAAT antibodies. Compared to untreated or albumin-controltreated graft recipients, which rejected islets at day 10, AATtreated mice displayed diminished cellular infiltrates and intact intragraft insulin production throughout treatment. Using peritoneal infiltration models, we demonstrate that AAT decreases allogeneic fibroblast-elicited natural-killer-cell influx by 89%, CD3-positive cell influx by 44%, and thioglycolate-elicited neutrophil emigration by 66%. ATT also extended islet viability in mice after streptozotocin-induced beta cell toxicity. In vitro, several islet responses to IL-1␤͞IFN␥ stimulation were examined. In the presence of AAT, islets displayed enhanced viability and inducible insulin secretion. Islets also released 36% less nitric oxide and 82% less macrophage inflammatory protein 1 ␣ and expressed 63% fewer surface MHC class II molecules. TNF␣ release from IL-1␤͞ IFN␥-stimulated islet cells was reduced by 99%, accompanied by an 8-fold increase in the accumulation of membrane TNF␣ on CD45-positive islet cells. In light of the established safety record and the nondiabetogenic potential of AAT, these data suggest that AAT may be beneficial as adjunctive therapy in patients undergoing islet transplantation.interleukin 1 ͉ nitric oxide ͉ TNF␣ I slet damage and an increased incidence of diabetes are associated with the use of immunosuppressive drugs in organ transplantation and present a major obstacle for clinically applicable human islet transplantation (1). Therefore, the advent of nondiabetogenic steroid-free, immunosuppressive treatment protocols, such as rapamycin-based protocols, have greatly facilitated human islet transplantation (reviewed in ref.2). However, although clinically effective, rapamycin-based protocols have been associated with an increased risk of hyperlipidemia and hypertension, limiting the applicability of islet transplantation to severe cases of diabetes type 1. Long-term follow-up studies reveal that the viability of engrafted islets is also compromised (3, 4).␣1-Antitrypsin (AAT), the major serum serine-protease inhibitor, inhibits the enzymatic activity of neutrophil elastase, cathepsin G, proteinase 3, thrombin, trypsin, and chymotrypsin (reviewed in ref. 5). AAT may facilitate the survival of islet transplants in engrafted patients, because the inhibitor prevents inflammatory cytokine production, blocks immune cell infiltration and function, inhibits complement activation, and delays the develop...

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Induction of ?1-antitrypsin synthesis in human articular chondrocytes by interleukin-6-type cytokines: Evidence for a local acute-phase response in the joint

Cited by 21 publications

References 58 publications

Regulation ofα1-proteinase inhibitor release by proinflammatory cytokines in human intestinal epithelial cells

Regulation ofα1-proteinase inhibitor release by proinflammatory cytokines in human intestinal epithelial cells

Recombinant adeno-associated virus-mediated alpha-1 antitrypsin gene therapy prevents type I diabetes in NOD mice

α1-Antitrypsin monotherapy prolongs islet allograft survival in mice

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