Download PDF
Thromb Haemost 2010; 104(04): 709-717
DOI: 10.1160/TH09-11-0805
Blood Coagulation, Fibrinolysis and Cellular Haemostasis
Schattauer GmbH

Factor XIII-A is involved in the regulation of gene expression in alternatively activated human macrophages

Dániel Töröcsik
1   Department of Biochemistry and Molecular Biology, University of Debrecen, Debrecen, Hungary
2   Department of Dermatology, University of Debrecen, Debrecen, Hungary
,
Lajos Széles
2   Department of Dermatology, University of Debrecen, Debrecen, Hungary
,
György Paragh Jr.
3   Department of Experimental Therapeutics, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, USA
,
Zsuzsa Rákosy
4   Department of Preventive Medicine Medical and Health Science Centre, University of Debrecen, Debrecen, Hungary
5   Public Health Research Group of the Hungarian Academy of Sciences, University of Debrecen, Debrecen, Hungary
,
Helga Bárdos
4   Department of Preventive Medicine Medical and Health Science Centre, University of Debrecen, Debrecen, Hungary
,
László Nagy
1   Department of Biochemistry and Molecular Biology, University of Debrecen, Debrecen, Hungary
,
Margit Balázs
4   Department of Preventive Medicine Medical and Health Science Centre, University of Debrecen, Debrecen, Hungary
5   Public Health Research Group of the Hungarian Academy of Sciences, University of Debrecen, Debrecen, Hungary
,
Aida Inbal
6   Thrombosis and Haemostasis Unit, Beilinson Hospital, Rabin Medical Centre, Petah Tikva, and Sackler Faculty of Medicine, Tel Aviv University, Israel
,
Róza Ádány
4   Department of Preventive Medicine Medical and Health Science Centre, University of Debrecen, Debrecen, Hungary
5   Public Health Research Group of the Hungarian Academy of Sciences, University of Debrecen, Debrecen, Hungary
› Author Affiliations Financial support:This work was supported by the Hungarian National Research Fund (contract number K81847 to R.A).
Further Information

Publication History

Received: 29 November 2009

Accepted after major revision: 18 May 2010

Publication Date:
24 November 2017 (online)

Also available at
    Permissions and Reprints

Summary

Factor XIII subunit A (FXIII-A) is one of the most overrepresented genes that is expressed during the alternative activation of macrophages. Based on its substrate profile and its cellular localisation, FXIII-A is thought to function as an intracellular/intranuclear transglutaminase. Our aim was to find role for the intracellular FXIII-A by comparing the microarray profiles of alternatively activated monocyte-derived macrophages. Microarray analyses of FXIII-A-deficient patients and healthy controls were evaluated, followed by functional clustering of the differentially expressed genes. After a 48-hour differentiation in the presence of interleukin 4 (IL4), 1,017 probes out of the 24,398 expressed in macrophages from FXIII-A- deficient samples were IL4 sensitive, while only 596 probes were IL4 sensitive in wild-type samples. Of these genes, 307 were induced in both the deficient and the wild-type macrophages. Our results revealed that FXIII-A has important role(s) in mediating gene expression changes in macrophages during alternative activation. Functional clustering of the target genes carried out using Cytoscape/BiNGO and Ingenuity Pathways Analysis programs showed that, in the absence of FXIII-A, the most prominent differences are related to immune functions and to wound response. Our findings suggest that functional impairment of macrophages at the level of gene expression regulation plays a role in the wound healing defects of FXIII-A-deficient patients.

Keywords

Factor XIII-A - macrophage - wound healing - interleukin 4

 

  • References

  • 1 de la Red G, Tassies D, Espinosa G. et al. Factor XIII-A subunit Val34Leu polymorphism is associated with the risk of thrombosis in patients with antiphospholipid antibodies and high fibrinogen levels. Thromb Haemost 2009; 101: 312-316.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 2 Rallidis LS, Politou M, Komporozos C. et al. Factor XIII Val34Leu polymorphism and the risk of myocardial infarction under the age of 36 years. Thromb Haemost 2008; 99: 1085-1089.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 3 Souri M, Koseki-Kuno S, Takeda N. et al. Male-specific cardiac pathologies in mice lacking either the A or B subunit of factor XIII. Thromb Haemost 2008; 99: 401-408.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 4 Voko Z, Bereczky Z, Katona E. et al. Factor XIII Val34Leu variant protects against coronary artery disease. A meta-analysis. Thromb Haemost 2007; 97: 458-463.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 5 Wypasek E, Stepien E, Pieculewicz M. et al. Factor XIII Val34Leu polymorphism and ischaemic stroke in patients with patent foramen ovale. Thromb Haemost 2009; 102: 1280-1282.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 6 Muszbek L, Adany R, Mikkola H. Novel aspects of blood coagulation factor XIII. I. Structure, distribution, activation, and function. Crit Rev Clin Lab Sci 1996; 33: 357-421.
    CrossrefPubMedGoogle Scholar
  • 7 Adany R, Bardos H, Antal M. et al. Factor XIII of blood coagulation as a nuclear crosslinking enzyme. Thromb Haemost 2001; 85: 845-851.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 8 Adany R, Kiss A, Muszbek L. Factor XIII: a marker of mono- and megakaryocytopoiesis. Br J Haematol 1987; 67: 167-172.
    CrossrefPubMedGoogle Scholar
  • 9 Adany R. Intracellular factor XIII: cellular distribution of factor XIII subunit a in humans. Sem Thromb Hemost 1996; 22: 399-408.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 10 Inbal A, Muszbek L, Lubetsky A. et al. Platelets but not monocytes contribute to the plasma levels of factor XIII subunit A in patients undergoing autologous peripheral blood stem cell transplantation. Blood Coagul Fibrinolysis 2004; 15: 249-253.
    CrossrefPubMedGoogle Scholar
  • 11 Muszbek L, Adany R, Szegedi G. et al. Factor XIII of blood coagulation in human monocytes. Thromb Res 1985; 37: 401-410.
    CrossrefPubMedGoogle Scholar
  • 12 Kaetsu H, Hashiguchi T, Foster D. et al. Expression and release of the a and b subunits for human coagulation factor XIII in baby hamster kidney (BHK) cells. J Biochem 1996; 119: 961-969.
    CrossrefPubMedGoogle Scholar
  • 13 Kiss F, Hevessy Z, Veszpremi A. et al. Leukemic lymphoblasts, a novel expression site of coagulation factor XIII subunit A. Thromb Haemost 2006; 96: 176-182.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 14 Gordon S, Taylor PR. Monocyte and macrophage heterogeneity. Nature Rev 2005; 5: 953-964.
    PubMedGoogle Scholar
  • 15 Torocsik D, Bardos H, Nagy L. et al. Identification of factor XIII-A as a marker of alternative macrophage activation. Cell Mol Life Sci 2005; 62: 2132-2139.
    CrossrefPubMedGoogle Scholar
  • 16 Chaitidis P, O’Donnell V, Kuban RJ. et al. Gene expression alterations of human peripheral blood monocytes induced by medium-term treatment with the TH2-cytokines interleukin-4 and –13. Cytokine 2005; 30: 366-377.
    CrossrefPubMedGoogle Scholar
  • 17 Sarvary A, Szucs S, Balogh I. et al. Possible role of factor XIII subunit A in Fcgamma and complement receptor-mediated phagocytosis. Cellular Immunol 2004; 228: 81-90.
    CrossrefPubMedGoogle Scholar
  • 18 Inbal A, Dardik R. Role of coagulation factor XIII (FXIII) in angiogenesis and tissue repair. Pathophysiol Haemost Thromb 2006; 35: 162-165.
    CrossrefPubMedGoogle Scholar
  • 19 Adany R, Bardos H. Factor XIII subunit A as an intracellular transglutaminase. Cell Mol Life Sci 2003; 60: 1049-1060.
    CrossrefPubMedGoogle Scholar
  • 20 Inbal A, Yee VC, Kornbrot N. et al. Factor XIII deficiency due to a Leu660Pro mutation in the factor XIII subunit-a gene in three unrelated Palestinian Arab families. Thromb Haemost 1997; 77: 1062-1067.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 21 Ivaskevicius V, Seitz R, Kohler HP. et al. International registry on factor XIII deficiency: a basis formed mostly on European data. Thromb Haemost 2007; 97: 914-921.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 22 Maere S, Heymans K, Kuiper M. BiNGO: a Cytoscape plugin to assess overrepresentation of gene ontology categories in biological networks. Bioinformatics (Oxford, England) 2005; 21: 3448-3449.
    CrossrefPubMedGoogle Scholar
  • 23 Goerdt S, Orfanos CE. Other functions, other genes: alternative activation of antigen-presenting cells. Immunity 1999; 10: 137-142.
    CrossrefPubMedGoogle Scholar
  • 24 Shimizu T, Hozumi K, Horiike S. et al. A covalently crosslinked histone. Nature 1996; 380: 32.
    CrossrefPubMedGoogle Scholar
  • 25 Adany R, Belkin A, Vasilevskaya T. et al. Identification of blood coagulation factor XIII in human peritoneal macrophages. Eur J Cell Biol 1985; 38: 171-173.
    PubMedGoogle Scholar
  • 26 Cohen I, Young-Bandala L, Blankenberg TA. et al. Fibrinoligase-catalyzed cross-linking of myosin from platelet and skeletal muscle. Arch Biochem Biophys 1979; 192: 100-111.
    CrossrefPubMedGoogle Scholar
  • 27 Asijee GM, Muszbek L, Kappelmayer J. et al. Platelet vinculin: a substrate of activated factor XIII. Biochim Biophys Acta 1988; 954: 303-308.
    CrossrefPubMedGoogle Scholar
  • 28 AbdAlla S, Lother H, Langer A. et al. Factor XIIIA transglutaminase crosslinks AT1 receptor dimers of monocytes at the onset of atherosclerosis. Cell 2004; 119: 343-354.
    CrossrefPubMedGoogle Scholar
  • 29 Zhu Y, Tassi L, Lane W. et al. Specific binding of the transglutaminase, platelet factor XIII, to HSP27. J Biol Chem 1994; 269: 22379-22384.
    PubMedGoogle Scholar
  • 30 Sane DC, Moser TL, Pippen AM. et al. Vitronectin is a substrate for transglutaminases. Biochem Biophys Res Commun 1988; 157: 115-120.
    CrossrefPubMedGoogle Scholar
  • 31 Koseki-Kuno S, Yamakawa M, Dickneite G. et al. Factor XIII A subunit-deficient mice developed severe uterine bleeding events and subsequent spontaneous miscarriages. Blood 2003; 102: 4410-4412.
    CrossrefPubMedGoogle Scholar
  • 32 Inbal A, Lubetsky A, Krapp T. et al. Impaired wound healing in factor XIII deficient mice. Thromb Haemost 2005; 94: 432-437.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 33 Seitz R, Duckert F, Lopaciuk S. et al. ETRO Working Party on Factor XIII questionnaire on congenital factor XIII deficiency in Europe: status and perspectives. Study Group. Sem Thromb Hemost 1996; 22: 415-418.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 34 Ballestar E, Abad C, Franco L. Core histones are glutaminyl substrates for tissue transglutaminase. J Biol Chem 1996; 271: 18817-18824.
    CrossrefPubMedGoogle Scholar
  • 35 Kim JH, Nam KH, Kwon OS. et al. Histone cross-linking by transglutaminase. Biochem Biophys Res Commun 2002; 293: 1453-1457.
    CrossrefPubMedGoogle Scholar
  • 36 Mann AP, Verma A, Sethi G. et al. Overexpression of tissue transglutaminase leads to constitutive activation of nuclear factor-kappaB in cancer cells: delineation of a novel pathway. Cancer Res 2006; 66: 8788-8795.
    CrossrefPubMedGoogle Scholar
  • 37 Ogawa T, Morioka Y, Inoue T. et al. Involvement of blood coagulation factor XIII in burn healing in the carbon tetrachloride-induced hepatic injury model in rats. Inflamm Res 1995; 44: 264-268.
    CrossrefPubMedGoogle Scholar
  • 38 Prince CW, Dickie D, Krumdieck CL. Osteopontin, a substrate for transglutaminase and factor XIII activity. Biochem Biophys Res Commun 1991; 177: 1205-1210.
    CrossrefPubMedGoogle Scholar
  • 39 Procyk R, Blomback B. Factor XIII-induced crosslinking in solutions of fibrinogen and fibronectin. Biochim Biophys Acta 1988; 967: 304-313.
    CrossrefPubMedGoogle Scholar
  • 40 Lynch GW, Slayter HS, Miller BE. et al. Characterization of thrombospondin as a substrate for factor XIII transglutaminase. J Biol Chem 1987; 262: 1772-1778.
    PubMedGoogle Scholar
  • 41 Akimov SS, Belkin AM. Cell surface tissue transglutaminase is involved in adhesion and migration of monocytic cells on fibronectin. Blood 2001; 98: 1567-1576.
    CrossrefPubMedGoogle Scholar