Skip to main content
SpringerLink
Log in

Immunohistochemical Localization of Human Kallikreins 6 and 10 in Pancreatic Islets

  • Published:
The Histochemical Journal Aims and scope Submit manuscript

Abstract

Tissue kallikreins are thought to be present in the pancreatic islets of Langerhans and to aid in the conversion of proinsulin to insulin. In recent immunohistochemical studies, we observed strong staining of the newly identified human kallikreins 6 and 10 (hK6 and hK10) in the islets of Langerhans. Here, we examine hK6 and hK10 immunoexpression in different types of islet cells of the endocrine pancreas, in order to obtain clues for hK6 and hK10 function in these cells. Ten cases of normal pancreatic tissue, two cases of nesidioblastosis, five insulin-producing tumours and one case of multiple endocrine neoplasia 1 syndrome, containing an insulin-, a somatostatin- and several glucagon-producing tumours, as well as tiny foci of endocrine dysplasia with different predominance of the secreted hormones (mainly glucagon and pancreatic polypeptide) were included in the study. A streptavidin–biotin–peroxidase and an alkaline phosphatase protocol, as well as a sequential immunoenzymatic double staining method were performed, using specific antibodies against hK6, hK10, insulin, glucagon, somatostatin, pancreatic polypeptide, and serotonin. hK6 and hK10 immunoexpression was observed in the islets of Langerhans, including the pancreatic polypeptide-rich islets, in the normal pancreas. Scattered hK6 and hK10 positive cells were localized in relationship with pancreatic acinar cells. In the exocrine pancreas, a cytoplasmic and/or brush border hK6 and hK10 immunoexpression was observed in the median and small sized pancreatic ducts, while the acinar cells were negative. Foci of nesidioblastosis and endocrine dysplasia expressed both kallikreins. hK6 and hK10 were also strongly and diffusely expressed throughout all insulin-, glucagon- and somatostatin-producing tumours. The double staining method revealed co-localization of each hormone and hK6/hK10 respectively, in the same cellular population, in the normal as well as in the diseased pancreas. Our results support the view that hK6 and hK10 may be involved in insulin and other pancreatic hormone processing and/or secretion, as well as in physiological functions related to the endocrine pancreas.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Anisowicz A, Sotiropoulou G, Stenman G, Mok SC, Sager R (1996) A novel protease homolog differentially expressed in breast and ovarian cancer. Mol Med 2: 624–636.

    CAS  PubMed  Google Scholar 

  • Bhoola KD, Figueroa CD, Worthy K (1992) Bioregulation of kinins: Kallikreins, kininogens, and kininases. Pharmacol Rev 44: 1–80.

    CAS  PubMed  Google Scholar 

  • Bothwell MA, Wilson WH, Shooter EM (1979) The relationship between glandular kallikrein and growth factor-processing proteases of mouse submaxillary gland. J Biol Chem 254: 7287–7294.

    CAS  PubMed  Google Scholar 

  • Chao J, Sostek M, Shimamoto K, Bank HL, Bigelow J, Margolius HS (1980) Kallikrein content of rat pancreatic acinar cells or islets by direct radioimmunoassay. Hoppe Seylers Z Physiol Chem 361: 1805–1810.

    CAS  PubMed  Google Scholar 

  • Dhanvantari S, Brubaker PL (1998) Proglucagon processing in an islet cell line: Effects of PC1 overexpression and PC2 depletion. Endocrinology 139: 1630–1637.

    Article  CAS  PubMed  Google Scholar 

  • Diamandis EP, Yousef GM, Luo LY, Magklara A, Obiezu CV (2000a) The newhuman kallikrein gene family: Implications in carcinogenesis. Trends Endocrinol Metab 11: 54–60.

    Article  CAS  PubMed  Google Scholar 

  • Diamandis EP, Yousef GM, Soosaipillai AR, Bunting P (2000b) Human kallikrein 6 (zyme/protease M/neurosin): A new serum biomarker of ovarian carcinoma. Clin Biochem 33: 579–583.

    Article  CAS  PubMed  Google Scholar 

  • Diamandis EP, Yousef GM, Soosaipillai AR, Grass L, Porter A, Little S, Sotiropoulou G (2000c) Immunofluorometric assay of human kallikrein 6 (zyme/protease M/neurosin) and preliminary clinical applications. Clin Biochem 33: 369–375.

    Article  CAS  PubMed  Google Scholar 

  • Dietl T, Kruck J, Fritz H (1978) Localization of kallikrein in porcine pancreas and submandibular gland as revealed by the indirect immunofluorescence technique. Hoppe Seylers Z Physiol Chem 359: 499–505.

    CAS  PubMed  Google Scholar 

  • Edlund H (1999) Pancreas: How to get there from the gut? Curr Opin Cell Biol 11: 663–668.

    Article  CAS  PubMed  Google Scholar 

  • Furuta M, Carroll R, Martin S, Swift HH, Ravazzola M, Orci L, Steiner DF (1998) Incomplete processing of proinsulin to insulin accompanied by elevation of Des-31,32 proinsulin intermediates in islets of mice lacking active PC2. J Biol Chem 273: 3431–3437.

    Article  CAS  PubMed  Google Scholar 

  • Goyal J, Smith KM, Cowan JM, Wazer DE, Lee SW, Band V (1998) The role for NES1 serine protease as a novel tumor suppressor. Cancer Res 58: 4782–4786.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  • Itoh Y, Tanaka S, Takekoshi S, Itoh J, Osamura RY (1996) Prohormone convertases (PC1/3 and PC2) in rat and human pancreas and islet cell tumors: Subcellular immunohistochemical analysis. Pathol Int 46: 726–737.

    Article  CAS  PubMed  Google Scholar 

  • Jaffe R, Hashida Y, Yunis EJ (1980) Pancreatic pathology in hyperinsulinemic hypoglycemia of infancy. Lab Invest 42: 356–365.

    CAS  PubMed  Google Scholar 

  • Jones TH, Figueroa CD, Smith C, Cullen DR, Bhoola KD (1990) Characterization of a tissue kallikrein in human prolactin-secreting adenomas. J Endocrinol 124: 327–331.

    Article  CAS  PubMed  Google Scholar 

  • Kraut H, Frey EK, Werle E (1930) Der Nachweis eines Kreislaufhormons in der Pankreasdruese. Hoppe-Seylers Z Phiol Chem 189: 97–106.

    CAS  Google Scholar 

  • Little SP, Dixon EP, Norris F, Buckley W, Becker GW, Johnson M, Dobbins JR, Wyrick T, Miller JR, MacKellar W, Hepburn D, Corvalan J, McClure D, Liu X, Stephenson D, Clements J, Johnstone EM (1997) Zyme, a novel and potentially amyloidogenic enzyme cDNA isolated from Alzheimer's disease brain. J Biol Chem 272: 25135–25142.

    Article  CAS  PubMed  Google Scholar 

  • Liu XL, Wazer DE, Watanabe K, Band V (1996) Identification of a novel serine protease-like gene, the expression of which is down-regulated during breast cancer progression. Cancer Res 56: 3371–3379.

    CAS  PubMed  Google Scholar 

  • Luo LY, Grass L, Diamandis EP (2000) The normal epithelial cell-specific 1 (NES1) gene is up-regulated by steroid hormones in the breast carcinoma cell line BT-474. Anticancer Res 20: 981–986.

    CAS  PubMed  Google Scholar 

  • Luo LY, Bunting P, Scorilas A, Diamandis EP (2001a) Human kallikrein 10: A novel tumor marker for ovarian carcinoma? Clin Chim Acta 306: 111-118.

    Article  CAS  PubMed  Google Scholar 

  • Luo LY, Grass L, Howarth DJ, Thibault P, Ong H, Diamandis EP (2001b) Immunofluorometric assay of human kallikrein 10 and its identification in biological fluids and tissues. Clin Chem 47: 237–246.

    CAS  PubMed  Google Scholar 

  • Luo LY, Rajpert-De Meyts ER, Jung K, Diamandis EP (2001c) Expression of the normal epithelial cell-specific 1 (NES1; KLK10) candidate tumour suppressor gene in normal and malignant testicular tissue. Br J Cancer 85: 220–224.

    Article  CAS  PubMed  Google Scholar 

  • Martella EM, Ferraro G, Azzoni C, Marignani M, Bordi C (1997) Pancreatic-polypeptide cell hyperplasia associated with pancreatic or duodenal gastrinomas. Hum Pathol 28: 149–153.

    Article  CAS  PubMed  Google Scholar 

  • Mason AJ, Evans BA, Cox DR, Shine J, Richards RI (1983) Structure of mouse kallikrein gene family suggests a role in specific processing of biologically active peptides. Nature 303: 300–307.

    Article  CAS  PubMed  Google Scholar 

  • Nie Y, Nakashima M, Brubaker PL, Li QL, Perfetti R, Jansen E, Zambre Y, Pipeleers D, Friedman TC (2000) Regulation of pancreatic PC1 and PC2 associated with increased glucagon-like peptide 1 in diabetic rats. J Clin Invest 105: 955-965.

    Article  CAS  PubMed  Google Scholar 

  • Oertel JE, Heffess CS, Oertel YC (1992) Pancreas. In: Stephen S, ed. Histology for Pathologists. New York: Raven Press, pp. 657–668.

    Google Scholar 

  • ole-MoiYoi OK, Pinkus GS, Spragg J, Austen KF (1979) Identification of human glandular kallikrein in the beta cell of the pancreas. N Engl J Med 300: 1289–1294.

    Article  PubMed  Google Scholar 

  • Orstavik TB, Brandtzaeg P, Nustad K, Pierce JV (1980) Immunohistochemical localization of kallikrein in human pancreas and salivary glands. J Histochem Cytochem 28: 557–562.

    CAS  PubMed  Google Scholar 

  • Orstavik TB, Brekke IB, Alumets J, Carretero OA (1981) Kallikrein in rat pancreatic tissue after beta cell destruction or acinar cell atrophy. J Histochem Cytochem 29: 1431–1436.

    CAS  PubMed  Google Scholar 

  • Peters J, Juergensen A, Kloeppel G (2000) Ontogeny, differentiation and growth of the endocrine pancreas. Virchows Arch 436: 527–538.

    Article  CAS  PubMed  Google Scholar 

  • Petraki CD, Karavana VN, Skoufogiannis PT, Little SP, Howarth DJ, Yousef GM, Diamandis EP (2001) The spectrum of human kallikrein 6 (zyme/protease M/neurosin) expression in human tissues as assessed by immunohistochemistry. J Histochem Cytochem 49: 1431–1441.

    CAS  PubMed  Google Scholar 

  • Petraki CD, Karavana VN, Luo LY, Diamandis EP (2002) Human kallikrein 10 expression in normal tissues by immunohistochemistry. J Histochem Cytochem 50: 1247–1261.

    CAS  PubMed  Google Scholar 

  • Pinkus GS, Maier M, Seldin DC, ole-MoiYoi OK, Austen KF, Spragg J (1983) Immunohistochemical localization of glandular kallikrein in the endocrine and exocrine human pancreas. J Histochem Cytochem 31: 1279–1288.

    CAS  PubMed  Google Scholar 

  • Rothenberg ME, Eilertson CD, Klein K, Zhou Y, Lindberg I, McDonald JK, Mackin RB, Noe BD (1995) Processing of mouse proglucagon by recombinant prohormone convertase 1 and immunopurified prohormone convertase 2 in vitro. J Biol Chem 270: 10136–10146.

    Article  CAS  PubMed  Google Scholar 

  • Rouille Y, Westermark G, Martin SK, Steiner DF (1994) Proglucagon is processed to glucagon by prohormone convertase PC2 in alpha TC1-6 cells. Proc Natl Acad Sci USA 91: 3242–3246.

    Article  CAS  PubMed  Google Scholar 

  • Steiner DF, Rouille Y, Gong Q, Martin S, Carroll R, Chan SJ (1996) The role of prohormone convertases in insulin biosynthesis: Evidence for inherited defects in their action in man and experimental animals. Diabetes Metab 22: 94–104.

    CAS  PubMed  Google Scholar 

  • Vio CP, Roa JP, Silva R, Powers CA (1990) Localization of immunoreactive glandular kallikrein in lactotrophs of the rat anterior pituitary. Neuroendocrinology 51: 10–14.

    Article  CAS  PubMed  Google Scholar 

  • Werle E (1934) Zur Kenntnis des Haushalts des Kallikreins. Biochem Z 269: 415–434.

    CAS  Google Scholar 

  • Yamashiro K, Tsuruoka N, Kodama S, Tsujimoto M, Yamamura Y, Tanaka T, Nakazato H, Yamaguchi N (1997) Molecular cloning of a novel trypsin-like serine protease (neurosin) preferentially expressed in brain. Biochim Biophys Acta 1350: 11–14.

    CAS  PubMed  Google Scholar 

  • Yoi OO, Seldin DC, Spragg J, Pinkus GS, Austen KF (1979) Sequential cleavage of proinsulin by human pancreatic kallikrein and a human pancreatic kininase. Proc Natl Acad Sci USA 76: 3612–3616.

    Article  CAS  PubMed  Google Scholar 

  • Yousef GM, Diamandis EP (2000) The expanded human kallikrein gene family: Locus characterization and molecular cloning of a new member, KLK-L3 (KLK9). Genomics 65: 184–194.

    Article  CAS  PubMed  Google Scholar 

  • Yousef GM, Diamandis EP (2001) The new human tissue kallikrein gene family: Structure, function, and association to disease. Endocr Rev 22: 184–204.

    Article  CAS  PubMed  Google Scholar 

  • Yousef GM, Luo LY, Scherer SW, Sotiropoulou G, Diamandis EP (1999) Molecular characterization of zyme/protease M/neurosin (PRSS9), a hormonally regulated kallikrein-like serine protease. Genomics 62: 251–259.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pathology, Evangelismos Hospital, Athens, Greece

    Constantina D. Petraki, Vasso N. Karavana & Kyriakos I. Revelos

  2. Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, Ont., Canada, M5G 1X5

    Liu-Ying Luo & Eleftherios P. Diamandis

  3. Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ont., Canada, M5G 1L5

    Liu-Ying Luo & Eleftherios P. Diamandis

Authors
  1. Constantina D. Petraki
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Vasso N. Karavana
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kyriakos I. Revelos
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Liu-Ying Luo
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Eleftherios P. Diamandis
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Petraki, C.D., Karavana, V.N., Revelos, K.I. et al. Immunohistochemical Localization of Human Kallikreins 6 and 10 in Pancreatic Islets. Histochem J 34, 313–322 (2002). https://doi.org/10.1023/A:1023394030036

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1023394030036

Keywords

Search

Navigation