Relationship between PK2 and number of Kupffer cells during the progression of liver fibrosis in patients with HBV
Relationship between PK2 and number of Kupffer cells during the progression of liver fibrosis in patients with HBV
Background/aim: This study aimed to investigate the potential regulatory role of prokineticin 2 (PK2) in modulation of the number andfunction of Kupffer cells (KCs) during the progression of liver fibrosis in patients with hepatitis B virus (HBV).Materials and methods: We obtained liver tissue sections from 200 patients with HBV undergoing surgical resection in our hospitalbetween January 2013 and July 2016. Of these 200 tissue sections, 150 were fibrosis tissues and 50 were hepatocellular carcinomatissues. Immunohistochemical evaluations were performed to assess the expression levels of CD68 and PK2 in the sections. The clinicalparameters of these 200 patients were also analyzed.Results: As a potential cytokine, PK2 was commonly expressed in KCs. In addition, a close correlation between PK2 and the number ofKCs during the progression of liver fibrosis in patients with HBV was found in this study.Conclusion: PK2 is expressed in KCs and participates in the progression of liver fibrosis after HBV infection. As a potential cytokine,PK2 modulates the number of KCs during fibrosis. Thus, PK2 most likely adjusts the number of M1 cells to modulate the role of KCs inthe progression of liver fibrosis after HBV infection.
___
- Fattovich G, Bortolotti F, Donato F. Natural history of chronic
hepatitis B: special emphasis on disease progression and prognostic factors. J Hepatol 2008; 48: 335-352.
- Croagh CM, Lubel JS. Natural history of chronic hepatitis B:
phases in a complex relationship. World J Gastroentero 2014;
20: 10395-10404.
- Pellicoro A, Ramachandran P, Iredale JP, Fallowfield JA. Liver
fibrosis and repair: immune regulation of wound healing in a
solid organ. Nat Rev Immunol 2014; 14: 181-194.
- Kisseleva T, Brenner DA. The phenotypic fate and functional
role for bone marrow-derived stem cells in liver fibrosis. J Hepatol 2012; 56: 965-972.
- Wynn TA, Ramalingam TR. Mechanisms of fibrosis: therapeutic translation for fibrotic disease. Nat Med 2012; 18: 1028-
1040.
- Ju C, Tacke F. Hepatic macrophages in homeostasis and liver
diseases: from pathogenesis to novel therapeutic strategies.
Cell Mol Immunol 2016; 13: 316-327.
- Bataller R, Brenner DA. Liver fibrosis. J Clin Invest 2005; 115:
209-218.
8. Wells RG. Mechanisms of liver fibrosis: new insights into an
old problem. Drug Discov Today 2006; 3: 489-495.
- Lee UE, Friedman SL. Mechanisms of hepatic fibrogenesis.
Best Pract Res Clin Gastroenterol 2011; 25: 195-206.
10. Friedman SL. Liver fibrosis -- from bench to bedside. J Hepatol
2003; 38 (Suppl. 1): S38-53.
- Tacke F, Zimmermann HW. Macrophage heterogeneity in liver
injury and fibrosis. J Hepatol 2014; 60: 1090-1096.
- Elsegood CL, Chan CW, Degli-Esposti MA, Wikstrom ME,
Domenichini A, Lazarus K, van Rooijen N, Ganss R, Olynyk
JK, Yeoh GC. Kupffer cell-monocyte communication is essential for initiating murine liver progenitor cell-mediated liver
regeneration. Hepatology 2015; 62: 1272-1284.
- Monnier J, Samson M. Cytokine properties of prokineticins.
FEBS J 2008; 275: 4014-4021.
- Giannini E, Lattanzi R, Nicotra A, Campese AF, Grazioli P,
Screpanti I, Balboni G, Salvadori S, Sacerdote P, Negri L. The
chemokine Bv8/prokineticin 2 is up-regulated in inflammatory
granulocytes and modulates inflammatory pain. P Natl Acad
Sci USA 2009; 106: 14646-14651.
- Martucci C, Franchi S, Giannini E, Tian H, Melchiorri P, Negri
L, Sacerdote P. Bv8, the amphibian homologue of the mammalian prokineticins, induces a proinflammatory phenotype of
mouse macrophages. Br J Pharmacol 2006; 147: 225-234.
- Melchiorri D, Bruno V, Besong G, Ngomba RT, Cuomo L, De
Blasi A, Copani A, Moschella C, Storto M, Nicoletti F et al. The
mammalian homologue of the novel peptide Bv8 is expressed
in the central nervous system and supports neuronal survival
by activating the MAP kinase/PI-3-kinase pathways. Eur J
Neurosci 2001; 13: 1694-1702.
- Monnier J, Piquet-Pellorce C, Feige JJ, Musso O, Clement B,
Turlin B, Theret N, Samson M. Prokineticin 2/Bv8 is expressed
in Kupffer cells in liver and is down regulated in human hepatocellular carcinoma. World J Gastroentero 2008; 14: 1182-
1191.
- Negri L, Lattanzi R, Giannini E, Colucci MA, Mignogna G,
Barra D, Grohovaz F, Codazzi F, Kaiser A, Kreil G et al. Biological activities of Bv8 analogues. Br J Pharmacol 2005; 146:
625-632.
- Negri L, Lattanzi R, Giannini E, Melchiorri P. Bv8/Prokineticin
proteins and their receptors. Life Sci 2007; 81: 1103-1116.
- Dorsch M, Qiu Y, Soler D, Frank N, Duong T, Goodearl A,
O’Neil S, Lora J, Fraser CC. PK1/EG-VEGF induces monocyte
differentiation and activation. J Leukoc Biol 2005; 78: 426-434.
- LeCouter J, Zlot C, Tejada M, Peale F, Ferrara N. Bv8 and endocrine gland-derived vascular endothelial growth factor stimulate hematopoiesis and hematopoietic cell mobilization. P Natl
Acad Sci USA 2004; 101: 16813-16818.
- Goodman ZD. Grading and staging systems for inflammation
and fibrosis in chronic liver diseases. J Hepatol 2007; 47: 598-
607.
- Fellay J, Thompson AJ, Ge D, Gumbs CE, Urban TJ, Shianna
KV, Little LD, Qiu P, Bertelsen AH, Watson M. ITPA gene variants protect against anaemia in patients treated for chronic
hepatitis C. Nature 2010; 464: 405-408.
- Wai CT, Greenson JK, Fontana RJ, Kalbfleisch JD, Marrero JA,
Conjeevaram HS, Lok AS. A simple noninvasive index can
predict both significant fibrosis and cirrhosis in patients with
chronic hepatitis C. Hepatology 2003; 38: 518-526.
- Strojnik T, Kavalar R, Zajc I, Diamandis EP, Oikonomopoulou
K, Lah TT. Prognostic impact of CD68 and kallikrein 6 in human glioma. Anticancer Res 2009; 29: 3269-3279.
- Chuang HM, Su HL, Li C, Lin SZ, Yen SY, Huang MH, Ho LI,
Chiou TW, Harn HJ. The role of butylidenephthalide in targeting the microenvironment which contributes to liver fibrosis
amelioration. Front Pharmacol 2016; 7: 112.
- Weiskirchen R. Hepatoprotective and anti-fibrotic agents: it’s
time to take the next step. Front Pharmacol 2015; 6: 303.
- Samuel CS, Summers RJ, Hewitson TD. Antifibrotic actions of
serelaxin - new roles for an old player. Trends Pharmacol Sci
2016; 37: 485-497.
- Mormone E, George J, Nieto N. Molecular pathogenesis of hepatic fibrosis and current therapeutic approaches. Chem Biol
Interact 2011; 193: 225-231.
- Mallat A, Lotersztajn S. Cellular mechanisms of tissue fibrosis.
5. Novel insights into liver fibrosis. Am J Physiol Cell Physiol
2013; 305: C789-799.
- Bilzer M, Roggel F, Gerbes AL. Role of Kupffer cells in host
defense and liver disease. Liver Int 2006; 26: 1175-1186.
- Jetten N, Verbruggen S, Gijbels MJ, Post MJ, De Winther MPJ,
Donners MMPC. Anti-inflammatory M2, but not pro-inflammatory M1 macrophages promote angiogenesis in vivo. Angiogenesis 2014; 17: 109-118.
- Schuppan D, Kim YO. Evolving therapies for liver fibrosis. J
Clin Invest 2013; 123: 1887-1901.
- Heymann F, Peusquens J, Ludwig-Portugall I, Kohlhepp M,
Ergen C, Niemietz P, Martin C, van Rooijen N, Ochando JC,
Randolph GJ et al. Liver inflammation abrogates immunological tolerance induced by Kupffer cells. Hepatology 2015; 62:
279-291.
- Herbert DR, Orekov T, Roloson A, Ilies M, Perkins C, O’Brien
W, Cederbaum S, Christianson DW, Zimmermann N, Rothenberg ME et al. Arginase I suppresses IL-12/IL-23p40-driven intestinal inflammation during acute schistosomiasis. J Immunol
2010; 184: 6438-6446.
- Sutherland TE, Maizels RM, Allen JE. Chitinases and chitinaselike proteins: potential therapeutic targets for the treatment of
T-helper type 2 allergies. Clin Exp Allergy 2009; 39: 943-955.
- Pesce JT, Ramalingam TR, Wilson MS, Mentink-Kane MM,
Thompson RW, Cheever AW, Urban JF Jr, Wynn TA. Retnla
(relmalpha/fizz1) suppresses helminth-induced Th2-type immunity. PLoS Pathog 2009; 5: e1000393.
- Reese TA, Liang HE, Tager AM, Luster AD, Van Rooijen N,
Voehringer D, Locksley RM. Chitin induces accumulation in
tissue of innate immune cells associated with allergy. Nature
2007; 447: 92-96.
- London A, Itskovich E, Benhar I, Kalchenko V, Mack M, Jung
S, Schwartz M. Neuroprotection and progenitor cell renewal
in the injured adult murine retina requires healing monocytederived macrophages. J Exp Med 2011; 208: 23-39.
- Xiao W, Hong H, Kawakami Y, Lowell CA, Kawakami T. Regulation of myeloproliferation and M2 macrophage programming in mice by Lyn/Hck, SHIP, and Stat5. J Clin Invest 2008;
118: 924-934.
- Gabbiani G. The myofibroblast in wound healing and fibrocontractive diseases. J Pathol 2003; 200: 500-503.
- Fiorentino DF, Zlotnik A, Vieira P, Mosmann TR, Howard M,
Moore KW, O’Garra A. IL-10 acts on the antigen-presenting
cell to inhibit cytokine production by Th1 cells. J Immunol
1991; 146: 3444-3451.
- Savage ND, de Boer T, Walburg KV, Joosten SA, van Meijgaarden K, Geluk A, Ottenhoff TH. Human anti-inflammatory macrophages induce Foxp3+GITR+CD25+ regulatory T cells,
which suppress via membrane-bound TGFβ-1. J Immunol
2008; 181: 2220-2226.
- Zhou QY. The prokineticins: a novel pair of regulatory peptides. Mol Interv 2006; 6: 330-338.
- Shojaei F, Wu X, Zhong C, Yu L, Liang XH, Yao J, Blanchard D,
Bais C, Peale FV, van Bruggen N et al. Bv8 regulates myeloidcell-dependent tumour angiogenesis. Nature 2007; 450: 825-
831.
- Zhong C, Qu X, Tan M, Meng YG, Ferrara N. Characterization
and regulation of bv8 in human blood cells. Clin Cancer Res
2009; 15: 2675-2684.
- Jenne CN, Kubes P. Immune surveillance by the liver. Nat Immunol 2013; 14: 996.