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01-11-2010 | Original Investigation

Glycyrrhizin inhibits highly pathogenic H5N1 influenza A virus-induced pro-inflammatory cytokine and chemokine expression in human macrophages

Authors: Martin Michaelis, Janina Geiler, Patrizia Naczk, Patchima Sithisarn, Henry Ogbomo, Behric Altenbrandt, Anke Leutz, Hans Wilhelm Doerr, Jindrich Cinatl Jr.

Published in: Medical Microbiology and Immunology | Issue 4/2010

Abstract

Hypercytokinaemia is thought to contribute to highly pathogenic H5N1 influenza A virus disease. Glycyrrhizin is known to exert immunomodulatory and anti-inflammatory effects and therefore a candidate drug for the control of H5N1-induced pro-inflammatory gene expression. Here, the effects of an approved parenteral glycyrrhizin preparation were investigated on H5N1 virus replication, H5N1-induced pro-inflammatory responses, and H5N1-induced apoptosis in human monocyte-derived macrophages. Glycyrrhizin 100 μg/ml, a therapeutically achievable concentration, impaired H5N1-induced production of CXCL10, interleukin 6, and CCL5 and inhibited H5N1-induced apoptosis but did not interfere with H5N1 replication. Global inhibition of immune responses may result in the loss of control of virus replication by cytotoxic immune cells including natural killer cells and cytotoxic CD8⁺ T-lymphocytes. Notably, glycyrrhizin concentrations that inhibited H5N1-induced pro-inflammatory gene expression did not affect cytolytic activity of natural killer cells. Since H5N1-induced hypercytokinaemia is considered to play an important role within H5N1 pathogenesis, glycyrrhizin may complement the arsenal of potential drugs for the treatment of H5N1 disease.

Cinatl J Jr, Michaelis M, Doerr HW (2007) The threat of avian influenza A (H5N1). Part I: epidemiologic concerns and virulence determinants. Med Microbiol Immunol 196:181–190CrossRefPubMed

Cinatl J Jr, Michaelis M, Doerr HW (2007) The threat of avian influenza a (H5N1): part II: clues to pathogenicity and pathology. Med Microbiol Immunol 196:191–201CrossRefPubMed

Cinatl J Jr, Michaelis M, Doerr HW (2007) The threat of avian influenza A (H5N1). Part III: antiviral therapy. Med Microbiol Immunol 196:203–212CrossRefPubMed

Cinatl J Jr, Michaelis M, Doerr HW (2007) The threat of avian influenza A (H5N1). Part IV: development of vaccines. Med Microbiol Immunol 196:213–225CrossRefPubMed

Maines TR, Szretter KJ, Perrone L, Belser JA, Bright RA, Zeng H, Tumpey TM, Katz JM (2008) Pathogenesis of emerging avian influenza viruses in mammals and the host innate immune response. Immunol Rev 225:68–84CrossRefPubMed

Michaelis M, Doerr HW, Cinatl J Jr (2009) Of chickens and men: avian influenza in humans. Curr Mol Med 9:131–151CrossRefPubMed

Taubenberger JK, Morens DM (2006) 1918 Influenza: the mother of all pandemics. Emerg Infect Dis 12:15–22PubMed

Hampson AW (2008) Vaccines for pandemic influenza. The history of our current vaccines, their limitations and the requirements to deal with a pandemic threat. Ann Acad Med Singap 37:510–517PubMed

Kieny MP, Fukuda K (2008) The pandemic influenza vaccine challenge. Vaccine 26:D3–D4CrossRefPubMed

10.

Sugrue RJ, Tan BH, Yeo DS, Sutejo R (2008) Antiviral drugs for the control of pandemic influenza virus. Ann Acad Med Singap 37:518–524PubMed

11.

Deyde VM, Xu X, Bright RA, Shaw M, Smith CB, Zhang Y, Shu Y, Gubareva LV, Cox NJ, Klimov AI (2007) Surveillance of resistance to adamantanes among influenza A(H3N2) and A(H1N1) viruses isolated worldwide. J Infect Dis 196:249–257CrossRefPubMed

12.

Saito R, Li D, Suzuki Y, Sato I, Masaki H, Nishimura H, Kawashima T, Shirahige Y, Shimomura C, Asoh N, Degawa S, Ishikawa H, Sato M, Shobugawa Y, Suzuki H (2007) High prevalence of amantadine-resistance influenza a (H3N2) in six prefectures, Japan, in the 2005–2006 season. J Med Virol 79:1569–1576CrossRefPubMed

13.

Saito R, Suzuki Y, Li D, Zaraket H, Sato I, Masaki H, Kawashima T, Hibi S, Sano Y, Shobugawa Y, Oguma T, Suzuki H (2008) Increased incidence of adamantane-resistant influenza A(H1N1) and A(H3N2) viruses during the 2006–2007 influenza season in Japan. J Infect Dis 197:630–632CrossRefPubMed

14.

Suzuki Y, Taira K, Saito R, Nidaira M, Okano S, Zaraket H, Suzuki H (2009) Epidemiologic study of influenza infection in Okinawa, Japan, from 2001 to 2007: changing patterns of seasonality and prevalence of amantadine-resistant influenza A virus. J Clin Microbiol 47:623–629CrossRefPubMed

15.

Dharan NJ, Gubareva LV, Meyer JJ, Okomo-Adhiambo M, McClinton RC, Marshall SA, St George K, Epperson S, Brammer L, Klimov AI, Bresee JS, Fry AM (2009) Infections with oseltamivir-resistant influenza A(H1N1) virus in the United States. JAMA 301:1034–1041CrossRefPubMed

16.

Hauge SH, Dudman S, Borgen K, Lackenby A, Hungnes O (2009) Oseltamivir-resistant influenza viruses A (H1N1), Norway, 2007–08. Emerg Infect Dis 15:155–162CrossRefPubMed

17.

Kramarz P, Monnet D, Nicoll A, Yilmaz C, Ciancio B (2009) Use of oseltamivir in 12 European countries between 2002 and 2007—lack of association with the appearance of oseltamivir-resistant influenza A(H1N1) viruses. Euro Surveill 14:pii=19112

18.

Moscona A (2009) Global transmission of oseltamivir-resistant influenza. N Engl J Med 360:953–956CrossRefPubMed

19.

Cheung CL, Rayner JM, Smith GJ, Wang P, Naipospos TS, Zhang J, Yuen KY, Webster RG, Peiris JS, Guan Y, Chen H (2006) Distribution of amantadine-resistant H5N1 avian influenza variants in Asia. J Infect Dis 193:1626–1629CrossRefPubMed

20.

McKimm-Breschkin JL, Selleck PW, Usman TB, Johnson MA (2007) Reduced sensitivity of influenza A (H5N1) to oseltamivir. Emerg Infect Dis 13:1354–1357PubMed

21.

de Jong MD (2008) H5N1 transmission and disease: observations from the frontlines. Pediatr Infect Dis J 27:S54–S56CrossRefPubMed

22.

Nguyen DH, Nguyen HH, Nguyen TV, Nguyen TM, Trinh TM, Nguyen QT, Van Dinh T, Shimbo T, Takahashi Y, Kato Y, Kawana A, Akita S, Kudo K (2009) Human infection with highly pathogenic avian influenza virus (H5N1) in northern Vietnam, 2004–2005. Emerg Infect Dis 15:19–23CrossRef

23.

Cinatl J Jr, Morgenstern B, Bauer G, Chandra P, Rabenau H, Doerr HW (2003) Glycyrrhizin, an active component of liquorice roots, and replication of SARS-associated coronavirus. Lancet 361:2045–2046CrossRefPubMed

24.

Cinatl J Jr, Michaelis M, Hoever G, Preiser W, Doerr HW (2005) Development of antiviral therapy for severe acute respiratory syndrome. Antiviral Res 66:81–97CrossRefPubMed

25.

Wang XQ, Li HY, Liu XY, Zhang FM, Li X, Piao YA, Xie ZP, Chen ZH, Li X (2006) The anti-respiratory syncytial virus effect of active compound of Glycyrrhiza GD4 in vitro. Zhong Yao Cai 29:692–694PubMed

26.

Asl MN, Hosseinzadeh H (2008) Review of pharmacological effects of Glycyrrhiza sp. and its bioactive compounds. Phytother Res 22:709–724CrossRefPubMed

27.

Fiore C, Eisenhut M, Krausse R, Ragazzi E, Pellati D, Armanini D, Bielenberg J (2008) Antiviral effects of Glycyrrhiza species. Phytother Res 22:141–148CrossRefPubMed

28.

Wolkerstorfer A, Kurz H, Bachhofner N, Szolar OH (2009) Glycyrrhizin inhibits influenza A virus uptake into the cell. Antivir Res 83:171–178CrossRefPubMed

29.

Beigel JH, Farrar J, Han AM, Hayden FG, Hyer R, de Jong MD, Lochindarat S, Nguyen TK, Nguyen TH, Tran TH, Nicoll A, Touch S, Yuen KY (2005) Avian influenza A (H5N1) infection in humans. N Engl J Med 353:1374–1385CrossRefPubMed

30.

de Jong MD, Simmons CP, Thanh TT, Hien VM, Smith GJ, Chau TN, Hoang DM, Chau NV, Khanh TH, Dong VC, Qui PT, Cam BV, Hado Q, Guan Y, Peiris JS, Chinh NT, Hien TT, Farrar J (2006) Fatal outcome of human influenza A (H5N1) is associated with high viral load and hypercytokinemia. Nat Med 12:1203–1207CrossRefPubMed

31.

Zheng BJ, Chan KW, Lin YP, Zhao GY, Chan C, Zhang HJ, Chen HL, Wong SS, Lau SK, Woo PC, Chan KH, Jin DY, Yuen KY (2008) Delayed antiviral plus immunomodulator treatment still reduces mortality in mice infected by high inoculum of influenza A/H5N1 virus. Proc Natl Acad Sci USA 105:8091–8096CrossRefPubMed

32.

van Riel D, Munster VJ, de Wit E, Rimmelzwaan GF, Fouchier RA, Osterhaus AD, Kuiken T (2006) H5N1 virus attachment to lower respiratory tract. Science 312:399CrossRefPubMed

33.

Deng R, Lu M, Korteweg C, Gao Z, McNutt MA, Ye J, Zhang T, Gu J (2008) Distinctly different expression of cytokines and chemokines in the lungs of two H5N1 avian influenza patients. J Pathol 216:328–336CrossRefPubMed

34.

Liem NT, Nakajima N, Le Phat P, Sato Y, Thach HN, Hung PV, San LT, Katano H, Kumasaka T, Oka T, Kawachi S, Matsushita T, Sata T, Kudo K, Suzuki K (2008) H5N1-infected cells in lung with diffuse alveolar damage in exudative phase from a fatal case in Vietnam. Jpn J Infect Dis 61:157–160PubMed

35.

Chen Y, Deng W, Jia C, Dai X, Zhu H, Kong Q, Huang L, Liu Y, Ma C, Li J, Xiao C, Liu Y, Wei Q, Qin C (2009) Pathological lesions and viral localization of influenza A (H5N1) virus in experimentally infected Chinese rhesus macaques: implications for pathogenesis and viral transmission. Arch Virol 154:227–233CrossRefPubMed

36.

Kwon YK, Lipatov AS, Swayne DE (2009) Bronchointerstitial pneumonia in guinea pigs following inoculation with H5N1 high pathogenicity avian influenza virus. Vet Pathol 46:138–141CrossRefPubMed

37.

Cheung CY, Poon LL, Lau AS, Luk W, Lau YL, Shortridge KF, Gordon S, Guan Y, Peiris JS (2002) Induction of proinflammatory cytokines in human macrophages by influenza A (H5N1) viruses: a mechanism for the unusual severity of human disease? Lancet 360:1831–1837CrossRefPubMed

38.

Guan Y, Poon LL, Cheung CY, Ellis TM, Lim W, Lipatov AS, Chan KH, Sturm-Ramirez KM, Cheung CL, Leung YH, Yuen KY, Webster RG, Peiris JS (2004) H5N1 influenza: a protean pandemic threat. Proc Natl Acad Sci USA 101:8156–8161CrossRefPubMed

39.

Woo PC, Tung ET, Chan KH, Lau CC, Lau SK, Yuen KY (2010) Cytokine profiles induced by the novel swine-origin influenza A/H1N1 virus: implications for treatment strategies. J Infect Dis 201:346–353CrossRefPubMed

40.

Geiler J, Michaelis M, Naczk P, Leutz A, Langer K, Doerr HW, Cinatl J Jr (2010) N-acetyl-L-cysteine (NAC) inhibits virus replication and expression of pro-inflammatory molecules in A549 cells infected with highly pathogenic H5N1 influenza A virus. Biochem Pharmacol 79:413–420CrossRefPubMed

41.

Reed LI, Muench H (1938) A simple method of estimating fifty per cent endpoints. Am J Hyg 27:493–497

42.

Michaelis M, Geiler J, Klassert D, Doerr HW, Cinatl J Jr (2009) Infection of human retinal pigment epithelial cells with influenza A viruses. Invest Ophthalmol Vis Sci 50:5419–5425CrossRefPubMed

43.

Osawa Y, Iho S, Takauji R, Takatsuka H, Yamamoto S, Takahashi T, Horiguchi S, Urasaki Y, Matsuki T, Fujieda S (2006) Collaborative action of NF-kappaB and p38 MAPK is involved in CpG DNA-induced IFN-alpha and chemokine production in human plasmacytoid dendritic cells. J Immunol 177:4841–4852PubMed

44.

Ogbomo H, Hahn A, Geiler J, Michaelis M, Doerr HW, Cinatl J Jr (2006) NK sensitivity of neuroblastoma cells determined by a highly sensitive coupled luminescent method. Biochem Biophys Res Commun 339:375–379CrossRefPubMed

45.

Ogbomo H, Michaelis M, Altenbrandt B, Doerr HW, Cinatl J Jr (2010) A novel immunomodulatory mechanism of ribavirin in suppressing natural killer cell function. Biochem Pharmacol 79:188–197CrossRefPubMed

46.

Zhou J, Law HK, Cheung CY, Ng IH, Peiris JS, Lau YL (2006) Differential expression of chemokines and their receptors in adult and neonatal macrophages infected with human or avian influenza viruses. J Infect Dis 194:61–70CrossRefPubMed

47.

van Rossum TG, Vulto AG, Hop WC, Schalm SW (1999) Pharmacokinetics of intravenous glycyrrhizin after single and multiple doses in patients with chronic hepatitis C infection. Clin Ther 21:2080–2090CrossRefPubMed

48.

Utsunomiya T, Kobayashi M, Pollard RB, Suzuki F (1997) Glycyrrhizin, an active component of licorice roots, reduces morbidity and mortality of mice infected with lethal doses of influenza virus. Antimicrob Agents Chemother 41:551–556PubMed

49.

Salomon R, Hoffmann E, Webster RG (2007) Inhibition of the cytokine response does not protect against lethal H5N1 influenza infection. Proc Natl Acad Sci USA 104:12479–12481CrossRefPubMed

50.

Droebner K, Reiling SJ, Planz O (2008) Role of hypercytokinemia in NF-kappaB p50-deficient mice after H5N1 influenza A virus infection. J Virol 82:11461–11466CrossRefPubMed

51.

Ehrhardt C, Ludwig S (2009) A new player in a deadly game: influenza viruses and the PI3K/Akt signalling pathway. Cell Microbiol 11:863–871CrossRefPubMed

52.

Aldridge JR Jr, Moseley CE, Boltz DA, Negovetich NJ, Reynolds C, Franks J, Brown SA, Doherty PC, Webster RG, Thomas PG (2009) TNF/iNOS-producing dendritic cells are the necessary evil of lethal influenza virus infection. Proc Natl Acad Sci USA 106:5306–5311CrossRefPubMed

53.

Fedson DS (2009) Confronting the next influenza pandemic with anti-inflammatory and immunomodulatory agents: why they are needed and how they might work. Influenza Other Respir Viruses 3:129–142CrossRef

Title: Glycyrrhizin inhibits highly pathogenic H5N1 influenza A virus-induced pro-inflammatory cytokine and chemokine expression in human macrophages
Authors: Martin Michaelis
Janina Geiler
Patrizia Naczk
Patchima Sithisarn
Henry Ogbomo
Behric Altenbrandt
Anke Leutz
Hans Wilhelm Doerr
Jindrich Cinatl Jr.
Publication date: 01-11-2010
Publisher: Springer-Verlag
Published in: Medical Microbiology and Immunology / Issue 4/2010
Print ISSN: 0300-8584
Electronic ISSN: 1432-1831
DOI: https://doi.org/10.1007/s00430-010-0155-0

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