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01.08.2005 | Article

Expression and secretion of alpha1-proteinase inhibitor are regulated by proinflammatory cytokines in human pancreatic islet cells

verfasst von: Domenico Bosco, Paolo Meda, Philippe Morel, David Matthey-Doret, Dorothée Caille, Christian Toso, Leo H. Bühler, Thierry Berney

Erschienen in: Diabetologia | Ausgabe 8/2005

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Abstract

Aims/hypothesis

Alpha1-proteinase inhibitor (α1-PI) has been considered a key player in inflammatory processes. In humans, the main production site of α1-PI is the liver, but other tissues, including pancreatic islets, also synthesise this molecule. The aims of this study were to assess the islet cell types that produce α1-PI, to determine whether α1-PI is actually secreted by islet cells, and to assess how its production and/or secretion are regulated.

Methods

Expression of α1-PI in human islet cells was assessed by immunofluorescence, electron microscopy and western blotting. Release of α1-PI was analysed by reverse haemolytic plaque assay and ELISA. The effects of cytokines on α1-PI synthesis and secretion were tested.

Results

Immunofluorescence showed that alpha and delta cells do express α1-PI, whereas beta cells do not. By electron microscopy, we demonstrated a colocalisation of α1-PI with glucagon and somatostatin within secretory granules. Immunolabelling also revealed localisation of α1-PI within the Golgi apparatus, related vesicles and lysosomal structures. The expression of α1-PI in islet cells was also demonstrated by western blotting and ELISA of protein extracts. ELISA and reverse haemolytic plaque assay showed that α1-PI is secreted into the culture medium. Treatment of islet cells with IL-1β and oncostatin M for 4 days increased the production and release of α1-PI.

Conclusions/interpretation

Our results demonstrate that α1-PI is expressed by the alpha and delta cells of human islets, and that proinflammatory cytokines enhance the production and release of this inhibitor.

Travis J, Salvesen GS (1983) Human plasma proteinase inhibitors. Annu Rev Biochem 52:655–709PubMed

Baumann H, Gauldie J (1994) The acute phase response. Immunol Today 15:74–80PubMed

Moshage H (1997) Cytokines and the hepatic acute phase response. J Pathol 181:257–266PubMed

Banda MJ, Rice AG, Griffin GL, Senior RM (1988) The inhibitory complex of human alpha 1-proteinase inhibitor and human leukocyte elastase is a neutrophil chemoattractant. J Exp Med 167:1608–1615PubMed

Parmar JS, Mahadeva R, Reed BJ et al (2002) Polymers of alpha(1)-antitrypsin are chemotactic for human neutrophils: a new paradigm for the pathogenesis of emphysema. Am J Respir Cell Mol Biol 26:723–730PubMed

Ikari Y, Fujikawa K, Yee KO, Schwartz SM (2000) Alpha(1)-proteinase inhibitor, alpha(1)-antichymotrypsin, or alpha(2)-macroglobulin is required for vascular smooth muscle cell spreading in three-dimensional fibrin gel. J Biol Chem 275:12799–12805PubMed

Joslin G, Krause JE, Hershey AD, Adams SP, Fallon RJ, Perlmutter DH (1991) Amyloid-beta peptide, substance P, and bombesin bind to the serpin-enzyme complex receptor. J Biol Chem 266:21897–21902PubMed

Van Molle W, Libert C, Fiers W, Brouckaert P (1997) Alpha 1-acid glycoprotein and alpha 1-antitrypsin inhibit TNF-induced but not anti-fas-induced apoptosis of hepatocytes in mice. J Immunol 159:3555–3564PubMed

Daemen MA, Heemskerk VH, van’t Veer C et al (2000) Functional protection by acute phase proteins alpha(1)-acid glycoprotein and alpha(1)-antitrypsin against ischemia/reperfusion injury by preventing apoptosis and inflammation. Circulation 102:1420–1426PubMed

10.

Brantly M (2002) Alpha1-antitrypsin: not just an antiprotease: extending the half-life of a natural anti-inflammatory molecule by conjugation with polyethylene glycol. Am J Respir Cell Mol Biol 27:652–654PubMed

11.

Cichy J, Potempa J, Chawla RK, Travis J (1995) Stimulatory effect of inflammatory cytokines on alpha 1-antichymotrypsin expression in human lung-derived epithelial cells. J Clin Invest 95:2729–2733PubMed

12.

Cichy J, Potempa J, Travis J (1997) Biosynthesis of alpha1-proteinase inhibitor by human lung-derived epithelial cells. J Biol Chem 272:8250–8255PubMed

13.

Sallenave JM, Tremblay GM, Gauldie J, Richards CD (1997) Oncostatin M, but not interleukin-6 or leukemia inhibitory factor, stimulates expression of alpha1-proteinase inhibitor in A549 human alveolar epithelial cells. J Interferon Cytokine Res 17:337–346PubMed

14.

Boutten A, Venembre P, Seta N et al (1998) Oncostatin M is a potent stimulator of alpha1-antitrypsin secretion in lung epithelial cells: modulation by transforming growth factor-beta and interferon-gamma. Am J Respir Cell Mol Biol 18:511–520PubMed

15.

Knoell DL, Ralston DR, Coulter KR, Wewers MD (1998) Alpha 1-antitrypsin and protease complexation is induced by lipopolysaccharide, interleukin-1beta, and tumor necrosis factor-alpha in monocytes. Am J Respir Crit Care Med 157:246–255PubMed

16.

Boskovic G, Twining SS (1998) Local control of alpha1-proteinase inhibitor levels: regulation of alpha1-proteinase inhibitor in the human cornea by growth factors and cytokines. Biochim Biophys Acta 1403:37–46PubMed

17.

Molmenti EP, Perlmutter DH, Rubin DC (1993) Cell-specific expression of alpha 1-antitrypsin in human intestinal epithelium. J Clin Invest 92:2022–34PubMed

18.

Fischer DC, Siebertz B, van de Leur E et al (1999) Induction of alpha1-antitrypsin synthesis in human articular chondrocytes by interleukin-6-type cytokines: evidence for a local acute-phase response in the joint. Arthritis Rheum 42:1936–1945PubMed

19.

Zhang S, Liu J, Dragunow M, Cooper GJ (2003) Fibrillogenic amylin evokes islet beta-cell apoptosis through linked activation of a caspase cascade and JNK1. J Biol Chem 278:52810–52819PubMed

20.

Jaikaran ET, Clark A (2001) Islet amyloid and type 2 diabetes: from molecular misfolding to islet pathophysiology. Biochim Biophys Acta 1537:179–203PubMed

21.

Eriksson S, Janciauskiene S, Lannfelt L (1995) Alpha 1-antichymotrypsin regulates Alzheimer beta-amyloid peptide fibril formation. Proc Natl Acad Sci U S A 92:2313–2317PubMed

22.

Bottino R, Fernandez LA, Ricordi C et al (1998) Transplantation of allogeneic islets of Langerhans in the rat liver: effects of macrophage depletion on graft survival and microenvironment activation. Diabetes 47:316–323PubMed

23.

Papaccio G, Pedulla M, Ammendola E, Todaro M (2002) Cytokine regulatory effects on alpha-1 proteinase inhibitor expression in NOD mouse islet endothelial cells. J Cell Biochem 85:123–130PubMed

24.

Lou J, Triponez F, Oberholzer J et al (1999) Expression of alpha-1 proteinase inhibitor in human islet microvascular endothelial cells. Diabetes 48:1773–1778PubMed

25.

Ray MB, Zumwalt RE (1986) Identification of alpha-1-proteinase inhibitor-containing cells in pancreatic islets. Cell Tissue Res 243:677–680PubMed

26.

Ray MB, Desmet VJ (1978) Immunohistochemical demonstration of alpha-1-antitrypsin in the islet cells of human pancreas. Cell Tissue Res 187:69–77PubMed

27.

Ricordi C, Lacy PE, Finke EH, Olack BJ, Scharp DW (1988) Automated method for isolation of human pancreatic islets. Diabetes 37:413–420PubMed

28.

Ris F, Hammar E, Bosco D et al (2002) Impact of integrin-matrix matching and inhibition of apoptosis on the survival of purified human beta-cells in vitro. Diabetologia 45:841–850PubMed

29.

Wright PH, Makulu DR, Posey IJ (1968) Guinea pig anti-insulin serum. Adjuvant effect of H. pertussis vaccine. Diabetes 17:513–516PubMed

30.

Liou W, Geuze HJ, Slot JW (1996) Improving structural integrity of cryosections for immunogold labeling. Histochem Cell Biol 106:41–58PubMed

31.

Tokuyasu K (1997) Immuno-cytochemistry on ultrathin cryosections. In: Spector, DL, Goodman, RD, Leinwand LA (eds) Cells, a laboratory manual. Laboratory Press, Cold Spring Harbor, pp 131.1–131.27

32.

Salomon D, Meda P (1986) Heterogeneity and contact-dependent regulation of hormone secretion by individual B cells. Exp Cell Res 162:507–520PubMed

33.

Ray MB, Desmet VJ, Gepts W (1977) Alpha-1-Antitrypsin immunoreactivity in islet cells of adult human pancreas. Cell Tissue Res 185:63–68PubMed

34.

Herrera PL (2000) Adult insulin- and glucagon-producing cells differentiate from two independent cell lineages. Development 127:2317–2322PubMed

35.

Herrera PL (2002) Defining the cell lineages of the islets of Langerhans using transgenic mice. Int J Dev Biol 46:97–103PubMed

36.

Glombik MM, Kromer A, Salm T, Huttner WB, Gerdes HH (1999) The disulfide-bonded loop of chromogranin B mediates membrane binding and directs sorting from the trans-Golgi network to secretory granules. EMBO J 18:1059–1070PubMed

37.

Misumi Y, Oda K, Fujiwara T, Takami N, Tashiro K, Ikehara Y (1991) Functional expression of furin demonstrating its intracellular localization and endoprotease activity for processing of proalbumin and complement pro-C3. J Biol Chem 266:16954–16959PubMed

38.

Rhodes CJ, Brennan SO, Hutton JC (1989) Proalbumin to albumin conversion by a proinsulin processing endopeptidase of insulin secretory granules. J Biol Chem 264:14240–14245PubMed

39.

Ohkubo K, Naito Y, Fujiwara T, Miyazaki J, Ikehara Y, Ono J (2003) Inhibitory effect of the alpha1-antitrypsin Pittsburgh type-mutant (alpha1-PIM/R) on proinsulin processing in the regulated secretory pathway of the pancreatic beta-cell line MIN6. Endocr J 50:9–20PubMed

40.

Steiner DF (1998) The proprotein convertases. Curr Opin Chem Biol 2:31–39PubMed

41.

Faust D, Raschke K, Hormann S, Milovic V, Stein J (2002) Regulation of alpha1-proteinase inhibitor release by proinflammatory cytokines in human intestinal epithelial cells. Clin Exp Immunol 128:279–284PubMed

42.

Amsterdam A, Sasson R (2002) The anti-inflammatory action of glucocorticoids is mediated by cell type specific regulation of apoptosis. Mol Cell Endocrinol 189:1–9PubMed

43.

Lambillotte C, Gilon P, Henquin JC (1997) Direct glucocorticoid inhibition of insulin secretion: an in vitro study of dexamethasone effects in mouse islets. J Clin Invest 99:414–423PubMed

44.

Corbett JA, Wang JL, Misko TP, Zhao W, Hickey WF, McDaniel ML (1993) Nitric oxide mediates IL-1 beta-induced islet dysfunction and destruction: prevention by dexamethasone. Autoimmunity 15:145–153PubMed

45.

Mauricio D, Andersen HU, Larsen CM, Karlsen AE, Mandrup-Poulsen T, Nerup J (1997) Dexamethasone prevents interleukin-1beta-mediated inhibition of rat islet insulin secretion without decreasing nitric oxide production. Cytokine 9:563–569PubMed

46.

Akiyama T, Takasawa S, Nata K et al (2001) Activation of Reg gene, a gene for insulin-producing beta-cell regeneration: poly(ADP-ribose) polymerase binds Reg promoter and regulates the transcription by autopoly(ADP-ribosyl)ation. Proc Natl Acad Sci U S A 98:48–53PubMed

47.

Fox CJ, Danska JS (1997) IL-4 expression at the onset of islet inflammation predicts nondestructive insulitis in nonobese diabetic mice. J Immunol 158:2414–2424PubMed

48.

Bolaffi JL, Rodd GG, Wang J, Grodsky GM (1994) Interrelationship of changes in islet nicotine adenine dinucleotide, insulin secretion, and cell viability induced by interleukin-1 beta. Endocrinology 134:537–542PubMed

49.

Delaney CA, Green MH, Lowe JE, Green IC (1993) Endogenous nitric oxide induced by interleukin-1 beta in rat islets of Langerhans and HIT-T15 cells causes significant DNA damage as measured by the ‘comet’ assay. FEBS Lett 333:291–295PubMed

50.

Mandrup-Poulsen T, Bendtzen K, Nerup J, Dinarello CA, Svenson M, Nielsen JH (1986) Affinity-purified human interleukin I is cytotoxic to isolated islets of Langerhans. Diabetologia 29:63–67PubMed

51.

Hohmeier HE, Tran VV, Chen G, Gasa R, Newgard CB (2003) Inflammatory mechanisms in diabetes: lessons from the beta-cell. Int J Obes Relat Metab Disord 27(Suppl 3):S12–S16PubMed

52.

Choi SE, Choi KM, Yoon IH et al (2004) IL-6 protects pancreatic islet beta cells from pro-inflammatory cytokines-induced cell death and functional impairment in vitro and in vivo. Transpl Immunol 13:43–53PubMed

53.

Hall P, Tryon E, Nikolai TF, Roberts RC (1986) Functional activities and nonenzymatic glycosylation of plasma proteinase inhibitors in diabetes. Clin Chim Acta 160:55–62PubMed

54.

Finotti P, Piccoli A, Carraro P (1992) Alteration of plasma proteinase–antiproteinase system in type 1 diabetic patients. Influence of sex and relationship with metabolic control. Diabetes Res Clin Pract 18:35–42PubMed

55.

Sandler M, Gemperli BM, Hanekom C, Kuhn SH (1988) Serum alpha 1-protease inhibitor in diabetes mellitus: reduced concentration and impaired activity. Diabetes Res Clin Pract 5:249–255PubMed

Titel: Expression and secretion of alpha1-proteinase inhibitor are regulated by proinflammatory cytokines in human pancreatic islet cells
verfasst von: Domenico Bosco
Paolo Meda
Philippe Morel
David Matthey-Doret
Dorothée Caille
Christian Toso
Leo H. Bühler
Thierry Berney
Publikationsdatum: 01.08.2005
Verlag: Springer-Verlag
Erschienen in: Diabetologia / Ausgabe 8/2005
Print ISSN: 0012-186X
Elektronische ISSN: 1432-0428
DOI: https://doi.org/10.1007/s00125-005-1816-1

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Expression and secretion of alpha1-proteinase inhibitor are regulated by proinflammatory cytokines in human pancreatic islet cells