The mRNAs of Prekallikrein, Factors XI and XII, and Kininogen, Components of the Contact Phase Cascade Are Differentially Expressed in Multiple Non-hepatic Human Tissues

Summary

Recently RT-PCR studies had demonstrated the expression of plasma prekallikrein (PPK) mRNA in extrahepatic tissues. The questions arose whether that is illegitimate or regular expression, and whether the mRNAs of blood coagulation factors XI and XII, and high molecular weight kininogen, components of the contact activation cascade of blood coagulation are also expressed in non-hepatic tissues. These questions were addressed in the present study by employing quantitative RT-PCR. The relative mRNA levels of the respective proteins determined in 16 human tissues indicate legitimate extrahepatic transcription of at least three of the genes. Transcription of all genes was highest in the liver, but only PPK mRNA was detected in all 16 tissues, especially high levels in pancreas, kidney, testis, spleen and prostate. We conclude from these results that PPK is synthesized in significant amounts in non-hepatic tissues and that this locally synthesized PPK may have special local functions.

Key words

Extrahepatic expression of contact activation proteins - illegitimate transcription - quantitative RT-PCR - TaqMan technique

• References

• 1 Schapira M, Despland E, Scott CF, Boxer LA, Colman RW. Purified human plasma kallikrein aggregates human blood neutrophils. J Clin Invest 1982; 69: 1199-202.
• 2 Schapira M, Scott CF, Boxer LA, Colman RW. Activation of human polymorphonuclear leukocytes by purified human plasma kallikrein. Adv Exp Med Biol 1983; 156: 747-53.
• 3 Wachtfogel YT, Kucich U, James HL, Scott CF, Schapira M, Zimmerman M, Cohen AB, Colman RW. Human plasma kallikrein releases neutrophil elastase during blood coagulation. J Clin Invest 1983; 72: 1672-7.
• 4 DiScipio RG. The activation of the alternative pathway C3 convertase by human plasma kallikrein. Immunology 1982; 45: 587-95.
• 5 Ghebrehiwet B, Silverberg M, Kaplan AP. Activation of the classical pathway of complement by Hageman factor fragment. J Exp Med 1981; 153: 665-76.
• 6 Ghebrehiwet B, Randazzo BP, Dunn JT, Silverberg M, Kaplan AP. Mechanisms of activation of the classical pathway of complement by Hageman factor fragment. J Clin Invest 1983; 71: 1450-6.
• 7 Ichinose A, Fujikawa K, Suyama T. The activation of pro-urokinase by plasma kallikrein and its inactivation by thrombin. J Biol Chem 1986; 261: 3486-9.
• 8 Hauert J, Nicoloso G, Schleuning WD, Bachmann F, Schapira M. Plasminogen activators in dextran sulfate-activated euglobulin fractions: a molecular analysis of factor XII- and prekallikrein-dependent fibrinolysis. Blood 1989; 73: 994-9.
• 9 Lin Y, Harris RB, Yan W, McCrae KR, Zhang H, Colman RW. High molecular weight kininogen peptides inhibit the formation of kallikrein on endothelial cell surfaces and subsequent urokinase-dependent plasmin formation. Blood 1997; 90: 690-7.
• 10 Bhoola KD, Figueroa CD, Worthy K. Bioregulation of Kinins: Kallikreins, Kininogens, and Kininases. Pharmacol Rev 1992; 44: 1-80.
• 11 Colman RW, Schmaier AH. Contact system: a vascular biology modulator with anticoagulant, profibrinolytic, antiadhesive, and proinflammatory attributes. Blood 1997; 90: 3819-43.
• 12 Ciechanowicz A, Bader M, Wagner J, Ganten D. Extra-hepatic transcription of plasma prekallikrein gene in human and rat tissues. Biochem Biophys Res Commun 1993; 197: 1370-6.
• 13 Hermann A, Buchinger P, Somlev B, Rehbock J. High and low molecular weight kininogen and plasma prekallikrein/plasma kallikrein in villous capillaries of human term placenta. Placenta 1996; 17: 223-30.
• 14 Hermann A, Arnhold M, Kresse H, Neth P, Fink E. Expression of plasma prekallikrein mRNA in human nonhepatic tissues and cell lineages suggests special local functions of the enzyme. Biol Chem 1999; 380: 1097-102.
• 15 Chelly J, Concordet JP, Kaplan JC, Kahn A. Illegitimate transcription: transcription of any gene in any cell type. Proc Natl Acad Sci USA 1989; 86: 2617-21.
• 16 Heid CA, Stevens J, Livak KJ, Williams PM. Real time quantitative PCR. Genome Res 1996; 6: 986-94.
• 17 Holland PM, Abramson RD, Watson R, Gelfand DH. Detection of specific polymerase chain reaction product by utilizing the 5′ 3′ exonuclease activity of Thermus aquaticus DNA polymerase. Proc Natl Acad Sci USA 1991; 88: 7276-80.
• 18 Köhler T. General aspects and chances of nucleic acid quantitation by PCR. In: Quantitation of mRNA by Polymerase Chain Reaction. Nonradioactive PCR Methods. Köhler Th, Lassner D, Rost A-K, Thamm B, Pustowoit B, Remke H, eds. Berlin: Springer; 1995: 3-26.
• 19 Müller-Berghaus G, Pötzsch B. Hämostaseologie. Heidelberg: Springer; 1999: 122-48.
• 20 Gordon EM, Gallagher CA, Johnson TR, Blossey BK, Ilan J. Hepatocytes express blood coagulation factor XII (Hageman factor). J Lab Clin Med 1990; 115: 463-9.
• 21 Kaplan AP, Joseph K, Shibayama Y, Nakazawa Y, Ghebrehiwet B, Reddigari S, Silverberg M. Bradykinin formation – Plasma and tissue pathways and cellular interactions. Clin Rev Allergy Immunol 1998; 16: 403-29.
• 22 Hermann A, Arnhold M, Kresse H, Neth P, Fink E. Expression of components of the kallikrein-kinin system in human cell lines. Immunopharmacology 1999; 45: 135-9.
• 23 Hallbach J, Adams G, Wirthensohn G, Guder GW. Quantification of kininogen in human renal medulla. Biol Chem Hoppe-Seyler 1987; 368: 1151-5.
• 24 Figueroa CD, Gonzalez CB, Müller-Esterl W, Bhoola KD. Cellular localization of human kininogens. Agents Actions Suppl 1992; 38: 617-26.
• 25 Hermann A, Braun A, Figueroa CD, Müller-Esterl W, Fritz H, Rehbock J. Expression and cellular localization of kininogens in the human kidney. Kidney Int 1996; 50: 79-84.
• 26 Seidah NG, Paquin J, Hamelin J, Benjannet S, Chretien M. Structural and immunological homology of human and porcine pituitary and plasma IRCM-serine protease 1 to plasma kallikrein: marked selectivity for pairs of basic residues suggests a widespread role in pro-hormone and pro-enzyme processing. Biochimie 1988; 70: 33-46.
• 27 Hecquet C, Tan FL, Marcic BM, Erdös EG. Human bradykinin B2 receptor is activated by kallikrein and other serine proteases. Mol Pharmacol 2000; 58: 828-36.
• 28 Dery O, Corvera CU, Steinhoff M, Bunnett NW. Proteinase-activated receptors: novel mechanisms of signaling by serine proteases. Am J Physiol 1998; 274: C1429-52.