Advances in Clinical and Experimental Medicine

Title abbreviation: Adv Clin Exp Med
JCR Impact Factor (IF) – 1.736
5-Year Impact Factor – 2.135
Index Copernicus  – 168.52
MEiN – 70 pts

ISSN 1899–5276 (print)
ISSN 2451-2680 (online)
Periodicity – monthly

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Advances in Clinical and Experimental Medicine

2019, vol. 28, nr 8, August, p. 1101–1110

doi: 10.17219/acem/94160

Publication type: original article

Language: English

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IgG plasma cells initiate changes in the protein C system in mouse ulcerative colitis through CD14+CD64+ macrophage activation

Xu Hong Lin1,D, Hui Chao Wang2,B, Yong Yu Li3,E, Jun Ling Guo4,C, Yu Xia Li1,B, Guan Chang Cheng4,A, Dan Dan Wei1,F, Rui Lin Yang1,C, Jun Jie Zhang5,F, De Sheng Yang6,B, Bin Wang1,B, Xue Qun Ren5,A

1 Department of Clinical Laboratory, Translational Medicine Center, Huaihe Hospital Affiliated to Henan University, Kaifeng, China

2 Department of Nephrology, First Affiliated Hospital of Henan University, Kaifeng, China

3 Department of Pathophysiology, Tongji University School of Medicine, Shanghai, China

4 Department of Cardiovascular Medicine, Huaihe Hospital Affiliated to Henan University, Kaifeng, China

5 Department of General Surgery, Huaihe Hospital Affiliated to Henan University, Kaifeng, China

6 Department of Gastroenterology, Huaihe Hospital Affiliated to Henan University, Kaifeng, China


Background. Inhibition of the protein C system (PCS) might be one of the mechanisms of ulcerative colitis (UC).
Objectives. The aim of the study was to explore the role of IgG plasma cells in changes in the PCS in UC.
Material and Methods. Dextran sulfate sodium (DSS) was chosen to induce mouse UC. Inflammation was assessed using hematoxylin & eosin (H&E) staining and immunofluorescence. The profiling of colonic plasma cells and macrophages from colitis mice was analyzed with flow cytometry. After stimulation of macrophages with IgG type immune complex (IgG-IC), western blot was used to determine tumor necrosis factor α (TNF-α) and interleukin 6 (IL-6) protein levels. After co-incubation of colonic mucosa microvascular endothelial cells (MVECs) with TNF-α or IL-6, mitogen-activated protein kinase (MAPK) expression was detected.
Results. The DSS-colitis mice showed higher inflammatory indexes (p < 0.05 or p < 0.01), accompanied by greater infiltration of CD38+IgG+ plasma cells (p < 0.01), CD14+CD64+ macrophages (p < 0.01) and IgG-IC than healthy mice. Enhancement of TNF-α and IL-6 protein expression was demonstrated in this subset of macrophages when stimulated by IgG-IC (p < 0.01). After MVECs were incubated with TNF-α or IL-6, the expression of β-arrestin1, pP38 MAPK and pJNK MAPK exhibited an increase (p < 0.05 or p < 0.01), but downregulation of endothelial protein C receptor (EPCR) expression was observed (p < 0.05 or p < 0.01); this inhibition of EPCR expression was reversed by SB203580, SP600125 or U0126 (p < 0.05 or p < 0.01). In addition, changes in activated protein C (APC) presented results similar to those for EPCR expression (p < 0.05 or p < 0.01).
Conclusion. These results reveal that the PCS is inhibited during UC processing. There is a possibility that the interaction between IgG plasma cells and CD14+CD64+ macrophages, as well as further secretion of cytokines from CD14+CD64+ macrophages by the formation and stimulation of IgG-IC, subsequently influence MVECs through the β-arrestin-MAPK pathway. Enhancement of PCS activity may represent a novel approach for treating UC.

Key words

macrophages, ulcerative colitis, MAPK, protein C system, plasma cells

References (41)

  1. Baumgart DC, Sandbom WJ. Inflammatory bowel disease: Clinical aspects and established and evolving therapies. Lancet. 2007;369(9573):1641–1657.
  2. Lust M, Vulcano M, Danese S. The protein C pathway in inflammatory bowel disease: The missing link between inflammation and coagulation. Trends Mol Med. 2008;14(6):237–244.
  3. Tolstanova G, Deng X, French SW, et al. Early endothelial damage and increased colonic vascular permeability in the development of experimental ulcerative colitis in rats and mice. Lab Invest. 2012;92(1):9–21.
  4. Mosnier LO, Zlokovic BV, Griffin JH. The cytoprotective protein C pathway. Blood. 2007;109(8):3161–3172.
  5. Griffin JH, Zlokovic BV, Mosnier LO. Protein C anticoagulant and cytoprotective pathways. Int J Hematol. 2012;95(4):333–345.
  6. Lin XH, Wang HC, Wei DD, et al. Study of the change and role of protein C system in ulcerate colitis [in Chinese]. Sheng Li Xue Bao. 2015;67(2):214–224.
  7. Jinno Y, Ohtani H, Nakamura S, et al. Infiltration of CD19+ plasma cells with frequent labeling of Ki-67 in corticosteroid-resistant active ulcerative colitis. Virchows Arch. 2006;448(4):412–421.
  8. Schicho R, Bashashati M, Bawa M, et al. The atypical cannabinoid O-1602 protects against experimental colitis and inhibits neutrophil recruitment. Inflamm Bowel Dis. 2011;17(8):1651–1664.
  9. Hartmann G, Bidlingmaier C, Siegmund B, et al. Specific type IV phosphodiesterase inhibitor rolipram mitigates experimental colitis in mice. J Pharmacol Exp Ther. 2000;292(1):22–30.
  10. Kihara N, de la Fuente SG, Fujino K, Takahashi T, Pappas TN, Mantyh CR. Vanilloid receptor-1 containing primary sensory neurones mediate dextran sulfate sodium induced colitis in rats. Gut. 2003;52(5):713–719.
  11. Medina F, Segundo C, Campos-Caro A, Salcedo I, García-Poley A, ­Brieva JA. Isolation, maturational level, and functional capacity of human colon lamina propria plasma cells. Gut. 2003;52(3):383–389.
  12. Li YY, Cao MH, Goetz B, et al. The dual effect of cannabinoid receptor-1 deficiency on the murine postoperative ileus. PLoS One. 2013;8(7):e67427.
  13. Chen HL, Wang H, Li WL, et al. TNF-α expression and effects of Dachengqi Decoctionin compound in gut macrophages [in Chinese]. World Chin J Digestol. 2003;11(4):442–445.
  14. Uo M, Hisamatsu T, Miyoshi J, et al. Mucosal CXCR4+ IgG plasma cells contribute to the pathogenesis of human ulcerative colitis through FcγR-mediated CD14 macrophage activation. Gut. 2013;62(12):1734–1744.
  15. Li K, Feng JY, Li YY, et al. Anti-inflammatory role of Cannabidiol and O-1602 in Cerulein-induced acute pancreatitis in mice. Pancreas. 2013;42(1):123–129.
  16. Scaldaferri F, Sans M, Vetrano S, et al. Crucial role of the protein C pathway in governing microvascular inflammation in inflammatory bowel disease. J Clin Invest. 2007;117(7):1951–1960.
  17. Zhang X, Huang L, Lu G, Ge L, Hong Y, Hu Z. Amyloid β suppresses protein C activation through inhibition of the endothelial protein C receptor (EPCR). J Mol Neurosci. 2014;52(1):117–123.
  18. Lin XH, Guo JL, Wen YQ, et al. Role of IgG plasma cells in the change of protein C system in ulcerative colitis [in Chinese]. Sheng Li Xue Bao. 2017;69(2):172–182.
  19. Bernstein CN, Blanchard JF, Houston DS, Wajda A. The incidence of deep venous thrombosis and pulmonary embolism among patients with inflammatory bowel disease: A population based cohort study. Thromb Haemost. 2001;85(3):430–434.
  20. Grainge MJ, West J, Card TR. Venous thromboembolism during active disease and remission in inflammatory bowel disease: A cohort study. Lancet. 2010;375(9715):657–663.
  21. Kappelman MD, Horvath-Puho E, Sandler RS, et al. Thromboembolic risk among Danish children and adults with inflammatory bowel diseases: A population-based nationwide study. Gut. 2011;60(7):937–943.
  22. Murthy SK, Nguyen GC. Venous thromboembolism in inflammatory bowel disease: An epidemiological review. Am J Gastroenterol. 2011;106(4):713–718.
  23. Kume K, Yamasaki M, Tashiro M, et al. Activation of coagulation and fibrinolys is secondary to bowel inflammation in patients with ulcerative colitis. Intern Med. 2007;46(17):1323–1329.
  24. Shi YH, Huang PX, Guo CY. Clinical study of platelet function in ulcerate colitis patients [in Chinese]. J Tongji Univ Med Sci. 2006;27(2):48–50.
  25. D’Alessio S, Genua M, Vetrano S. The protein C pathway in intestinal barrier function: Challenging the hemostasis paradigm. Ann N Y Acad Sci. 2012;1258(1):78–85.
  26. Gelzayd EA, Kraft SC, Fitch FW, Kirsner JB. Distribution of immunoglobulins in human rectal mucosa. II. Ulcerative colitis and abnormal mucosal control subjects. Gastroenterology. 1968;54(3):341–347.
  27. Strehl JD, Hartmann A, Agaimy A. Numerous IgG4-positive plasma cells are ubiquitous in diverse localised non-specific chronic inflammatory conditions and need to be distinguished from IgG4-related systemic disorders. J Clin Pathol. 2011;64(3):237–243.
  28. Halstensen TS, Das KM, Brandtzaeg P. Epithelial deposits of immunoglobulin G1 and activated complement colocalise with the M(r) 40 kD putative autoantigen in ulcerative colitis. Gut. 1993;34(5):650–657.
  29. Kamada N, Hisamatsu T, Okamoto S, et al. Unique CD14 intestinal macrophages contribute to the pathogenesis of Crohn disease via IL-23/IFN-gamma axis. J Clin Invest. 2008;118(6):2269–2280.
  30. Olejár T, Matej R, Zadinová M, Poucková P. Expression of proteinase activated receptor-2 during taurocholate induced acute pancreatitic lesion development. Int J Gastrointest Cancer. 2001;30(3):113–122.
  31. Levi M, van der Poll T, ten Cate H, van Deventer SJ. The cytokine-mediated imbalance between coagulant and anticoagulant mechanisms in sepsis and endotoxaemia. Eur J Clin Invest. 1997;27(1):3–9.
  32. Bierhaus A, Zhang Y, Deng Y, et al. Mechanism of the tumor necrosis factor alpha-mediated induction of endothelial tissue factor. J Biol Chem. 1995;270(44):26419–26432.
  33. Wakeman D, Schneider JE, Liu J, et al. Deletion of p38-alpha mitogen-activated protein kinase within the intestinal epithelium promotes colon tumorigenesis. Surgery. 2012;152(2):286–293.
  34. Zhao X, Kang B, Lu C, et al. Evaluation of p38 MAPK pathway as a molecular signature in ulcerative colitis. J Proteome Res. 2011;10(5):2216–2225.
  35. Reinecke K, Eminel S, Dierck F, et al. The JNK inhibitor XG-102 protects against TNBS-induced colitis. PLoS One. 2012;7(3):e30985.
  36. Kersting S, Behrendt V, Kersting J, et al. The impact of JNK inhibitor D-JNKI-1 in a murine model of chronic colitis induced by dextran sulfate sodium. J Inflamm Res. 2013;6:71–81.
  37. Schwanke RC, Marcon R, Meotti FC, et al. Oral administration of the flavonoid myricitrin prevents dextran sulfate sodium-induced experimental colitis in mice through modulation of PI3K/Akt signaling pathway. Mol Nutr Food Res. 2013;57(11):1938–1949.
  38. Brown MD, Sacks DB. Protein scaffolds in MAP kinase signaling. Cell Signal. 2009;21(4):462–469.
  39. Lee T, Lee E, Arrollo D, et al. Non-hematopoietic β-arrestin1 confers protection against experimental colitis. J Cell Physiol. 2016;231(5):992–1000.
  40. Whalen EJ, Rajagopal S, Lefkowitz RJ. Therapeutic potential of betaarrestin-and G protein-biased agonists. Trends Mol Med. 2011;17(3):126–139.
  41. Lee T, Lee E, Irwin R, Lucas PC, McCabe LR, Parameswaran N. β-Arrestin-1 deficiency protects mice from experimental colitis. Am J Pathol. 2013;182(4):1114–1123.