Regulated de novo biosynthesis of fibrinogen in extrahepatic epithelial cells in response to inflammation

Summary

Hepatic fibrinogen (FBG) is upregulated during an acute phase response (APR) induced by glucocorticoids and interleukin (IL)-6. Furthermore, intestine and lung epithelium synthesize FBG after exposure to inflammatory mediators, and both plasma and lung cell-derived FBG, along with fibronectin, assemble in detergent-insoluble extracellular matrices (ECM) of pneumocytes and fibroblasts independent of thrombin or plasmin cleavage. An epitope cryptic in soluble FBG (β^15-21) but exposed in matrix-FBG and fibrin induces cell proliferation and actin cytoskeleton reorganization during wound repair and angiogenesis. Although fibrin(ogen) is involved in hemostasis and homeostasis, mechanisms regulating extrahepatic FBG expression remain unexplored. Herein we examined FBG production by lung compared to liver epithelial cell lines in response to dexamethasone (DEX)+IL-6. Regulated synthesis of HepG2-FBG follows the pathway shown for constitutive synthesis by liver epithelium. Constitutive A549-FBG expression was not detectable, however, intracellular FBG precursors in DEX+IL-6-treated A549 lung cells were similar to HepG2 cells with two notable exceptions. The relative rate of chain synthesis in HepG2 cells was unequal, whereas nascent synthesis of all three chains occurred at equivalent rates in stimulated A549 cells. Unlike HepG2 cells, which rapidly secreted intact FBG, nascent dimeric FBG accumulated in the A549 cell-associated fraction prior to release into medium. Furthermore, soluble A549-FBG was susceptible to thrombin and plasmin cleavage. Interestingly, many functionally diverse proteins possess FBG-related domains that direct cell-fate determination during development or wound repair, suggesting that extrahepatic FBG biosynthesis evoked only during inflammation plays such a role during localized injury and repair to restore tissue homeostasis.

Keywords

Extrahepatic fibrinogen - wound repair - lung epithelium - thrombin - extracellular matrix

• References

• 1 Bini A, Simpson-Haidaris PJ, Kudryk BJ. Fibrin/Fibrinogen. In: Bikfalvi A. editor. Encyclopedic Reference of Vascular Biology & Pathology. Berlin: Springer-Verlag; 2000: 372.
• 2 Hantgan RR, Simpson-Haidaris PJ, Francis CW. et al. Fibrinogen structure and physiology. In: Colman RW, Hirsh J, Marder VJ, Clowes AW, George JN. editors. Haemostasis and Thrombosis: Basic Principles and Clinical Practice. 4th ed. Philadelphia: Lippincott Williams & Wilkins; 2001: 203-232.
• 3 Otto JM, Grenett HE, Fuller GM. The coordinated regulation of fibrinogen gene transcription by hepatocyte-stimulating factor and dexamethasone. J Cell Biol 1987; 105: 1067-1072.
• 4 Simpson-Haidaris PJ, Courtney MA. Tissuespecific and ubiquitous expression of fibrinogen γ-chain mRNA. Blood Coag Fibrinoly 1990; 01: 433-437.
• 5 Courtney MA, Stoler MH, Marder VJ. et al. Developmental expression of mRNAs encoding platelet proteins in rat megakaryocytes. Blood 1991; 77: 560-568.
• 6 Haidaris PJ, Courtney MA. Liver-specific RNA processing of the ubiquitously transcribed rat fibrinogen gamma-chain gene. Blood 1992; 79: 1218-1224.
• 7 Simpson-Haidaris PJ, Wright TW, Earnest BJ. et al. Cloning and characterization of a lung-specific cDNA corresponding to the ‘Y chain of hepatic fibrinogen. Gene 1995; 167: 273-278.
• 8 Simpson-Haidaris PJ. Induction of fibrinogen biosynthesis and secretion from cultured pulmonary epithelial cells. Blood 1997; 89: 873-882.
• 9 Simpson-Haidaris PJ, Courtney MA, Wright TW. et al. Induction of fibrinogen expression in the lung epithelium during Pneumocystis carinii pneumonia. Infect Immun 1998; 66: 4431-4439.
• 10 Lee SY, Lee KP, Lim JW. Identification and biosynthesis of fibrinogen in human uterine cervix carcinoma cells. Thromb Haemostas 1996; 75: 466-470.
• 11 Molmenti EP, Ziambaras T, Perlmutter DH. Evidence for an acute phase response in human intestinal epithelial cells. J Biol Chem 1993; 268: 14116-24.
• 12 Guadiz G, Sporn LA, Simpson-Haidaris PJ. Thrombin cleavage-independent deposition of fibrinogen in extracellular matrices. Blood 1997; 90: 2644-2653.
• 13 Guadiz G, Sporn LA, Goss RA. et al. Polarized secretion of fibrinogen by lung epithelial cells. Am J Respir Cell Mol Biol 1997; 17: 60-69.
• 14 Rybarczyk BJ, Lawrence SO, Simpson-Haidaris PJ. Matrix-fibrinogen enhances wound closure by increasing both cell proliferation and migration. Blood 2003; 102: 4035-4043.
• 15 Nguyen MD, Simpson-Haidaris PJ. Cell typespecific regulation of fibrinogen expression in lung epithelial cells by dexamethasone and IL-1β. Am J Respir Cell Mol Biol 2000; 22: 209-217.
• 16 Yu S, Sher B, Kudryk B. et al. Fibrinogen precursors. Order of assembly of fibrinogen chains. J Biol Chem 1984; 259: 10574-81.
• 17 Odrljin TM, Shainoff JR, Lawrence SO. et al. Thrombin cleavage enhances exposure of a heparin binding domain in the N-terminus of the fibrin b chain. Blood 1996; 88: 2050-2061.
• 18 Pereira M, Rybarczyk BJ, Odrljin TM. et al. The incorporation of fibrinogen into extracellular matrix is dependent on active assembly of a fibronectin matrix. J Cell Sci 2002; 115: 609-617.
• 19 Lawrence SO, Wright TW, Francis CW. et al. Purification and functional characterization of homodimeric γB-γB fibrinogen from rat plasma. Blood 1993; 82: 2406-2413.
• 20 Wagner DD, Lawrence SO, Ohlsson-Wilhelm BM. et al. Topology and order of formation of interchain disulfide bonds in von Willebrand factor. Blood 1987; 69: 27-32.
• 21 Kudryk B, Rohoza A, Ahadi M. et al. Specificity of a monoclonal antibody for the NH2-terminal region of fibrin. Mol Immunol 1984; 21: 89-94.
• 22 Redman CM, Xia H. Fibrinogen biosynthesis. Assembly, intracellular degradation, and association with lipid synthesis and secretion. Ann N Y Acad Sci 2001; 936: 480-495.
• 23 Huang S, Mulvihill ER, Farrell DH. et al. Biosynthesis of human fibrinogen. Subunit interactions and potential intermediates in the assembly. J Biol Chem 1993; 268: 8919-8926.
• 24 Huang S, Cao Z, Chung DW. et al. The role of betagamma and alphagamma complexes in the assembly of human fibrinogen. J Biol Chem 1996; 271: 27942-7.
• 25 Chung DW, Davie EW. gamma and gamma’ chains of human fibrinogen are produced by alternative mRNA processing. Biochemistry 1984; 23: 4232-4236.
• 26 Nickerson JM, Fuller GM. In vitro synthesis of rat fibrinogen: identification of preAcα, preBβ, and preγ polypeptides. Proc Natl Acad Sci USA 1981; 78: 303-307.
• 27 Xia H, Redman CM. Differential degradation of the three fibrinogen chains by proteasomes: involvement of Sec61p and cytosolic Hsp70. Arch Biochem Biophys 2001; 390: 137-145.
• 28 Crestani B, Cornillet P, Dehoux M. et al. Alveolar type II epithelial cells produce IL-6 in vitro and in vivo. Regulation by alveolar macrophage secretory products. J Clin Invest 1994; 94: 731-740.
• 29 Chen W, Havell EA, Gigliotti F. et al. IL-6 production in a murine model of Pneumocystis carinii pneumonia: relation to resistance and inflammatory response. Infect Immun 1993; 61: 97-102.
• 30 Yang F, Friedrichs WE, Navarijo-Ashbaugh AL. et al. Cell type-specific and inflammatory-induced expression of haptoglobin gene in lung. Lab Invest 1995; 73: 433-440.
• 31 Li JJ, Sanders RL, McAdam KP. et al. Impact of C-reactive protein (CRP) on surfactant function. J Trauma-Injury Infect Crit Care 1989; 29: 1690-1697.
• 32 Dentener MA, Vreugdenhil AC, Hoet PH. et al. Production of the acute-phase protein lipopolysaccharide-binding protein by respiratory type II epithelial cells: implications for local defense to bacterial endotoxins. Am J Respir Cell Mol Biol 2000; 23: 146-153.
• 33 Ray A, Ray BK. A novel cis-acting element is essential for cytokine-mediated transcriptional induction of the serum amyloid A gene in nonhepatic cells. Mol Cell Biol 1996; 16: 1584-1594.
• 34 Solito E, de Coupade C, Parente L. et al. IL-6 stimulates annexin 1 expression and translocation and suggests a new biological role as class II acute phase protein. Cytokine 1998; 10: 514-521.
• 35 Venembre P, Boutten A, Seta N. et al. Secretion of a1-antitrypsin by alveolar epithelial cells. FEBS Lett 1994; 346: 171-174.
• 36 Idell S, Koenig KB, Fair DS. et al. Serial abnormalities of fibrin turnover in evolving adult respiratory distress syndrome. Am J Physiol 1991; 261: L240-8.