Expression of arginase I and inducible nitric oxide synthase in the peripheral blood and lymph nodes of HIV‑positive patients

Zhang,Naichun; Deng,Jianning; Wu,Fengyao; Lu,Xiangchan; Huang,Lei; Zhao,Min

doi:10.3892/mmr.2015.4601

Expression of arginase I and inducible nitric oxide synthase in the peripheral blood and lymph nodes of HIV‑positive patients

Authors:
- Naichun Zhang
- Jianning Deng
- Fengyao Wu
- Xiangchan Lu
- Lei Huang
- Min Zhao
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Affiliations: Treatment and Research Center for Infectious Diseases, The 302 Hospital of PLA, Beijing 100039, P.R. China, AIDS Department, The 4th People's Hospital of Nanning/Guangxi AIDS Clinical Treatment Center, Nanning, Guangxi 530023, P.R. China
Published online on: November 23, 2015 https://doi.org/10.3892/mmr.2015.4601
Pages: 731-743
Copyright: © Zhang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Arginase I (Arg I) and inducible nitric oxide synthase (iNOS) are important in regulating immune functions through their metabolites. Previous studies have revealed that the expression of Arg I is increased and the expression of iNOS is reduced in the serum and peripheral blood mononuclear cells of human immunodeficiency virus (HIV)‑infected patients. As one of the most important immune organs and HIV replication sites, whether similar changes are present in the lymph nodes following HIV infection remains to be elucidated. To investigate this, the present study collected lymph node and blood specimens from 52 HIV‑infected patients to measure the expression levels of Arg I and iNOS by immunohistochemistry and fluoresence‑based flow cytometry. Compared with control subjects without HIV infection, the patients with HIV had significantly higher expression levels of Arg I in the lymph nodes and higher frequencies of Arg I+ CD4+ T cells and CD8+ T cells in the blood and lymph nodes, and these results were contrary the those of iNOS in the corresponding compartments. The expression levels of Arg I in the lymph nodes and blood were negatively associated with peripheral CD4+ T cell count and positively associated with viral load. However, the expression levels of iNOS in the lymph nodes and blood were positively associated with peripheral CD4+ T cell count and negatively associated with viral load. These results showed that alterations in the expression levels of Arg I and iNOS in the peripheral T cells and peripheral nodes of HIV infected patients are associated with disease progression in these patients. These results indicate a potential to therapeutic strategy for delaying disease progression through regulating and manipulating the expression levels of Arg I and iNOS in patients infected with HIV.

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1	Chen Q, Li Y, Su X, Hao M, Lu H and He X: Epidemiological analysis on recent infected HIV-1 patients among newly reported HIV cases in Beijing, from 2009 to 2011. Zhonghua Liu Xing Bing Xue Za Zhi. 35:53–56. 2014.In Chinese. PubMed/NCBI
2	Deeks SG: HIV: How to escape treatment. Nature. 477:36–37. 2011. View Article : Google Scholar : PubMed/NCBI
3	Lloyd A: HIV infection and AIDS. P N G Med J. 39:174–180. 1996.PubMed/NCBI
4	Hazenberg MD, Otto SA, van Benthem BH, Roos MT, Coutinho RA, Lange JM, Hamann D, Prins M and Miedema F: Persistent immune activation in HIV-1 infection is associated with progression to AIDS. AIDS. 17:1881–1888. 2003. View Article : Google Scholar : PubMed/NCBI
5	Munder M: Arginase: An emerging key player in the mammalian immune system. Br J Pharmacol. 158:638–651. 2009. View Article : Google Scholar : PubMed/NCBI
6	Abebe T, Takele Y, Weldegebreal T, Cloke T, Closs E, Corset C, Hailu A, Hailu W, Sisay Y, Corware K, et al: Arginase activity - a marker of disease status in patients with visceral leishmaniasis in ethiopia. PLoS Negl Trop Dis. 7:e21342013. View Article : Google Scholar : PubMed/NCBI
7	Nieves CJ Jr and Langkamp-Henken B: Arginine and immunity: A unique perspective. Biomed Pharmacother. 56:471–482. 2002. View Article : Google Scholar : PubMed/NCBI
8	Pavanelli WR, Gutierrez FR, Silva JJ, Costa IC, Menezes MC, Oliveira FJ, Itano EN and Watanabe MA: The effects of nitric oxide on the immune response during giardiasis. Braz J Infect Dis. 14:606–612. 2010. View Article : Google Scholar
9	Herrera-Ortiz A, Martinez-Barnetche J, Smit N, Rodriguez MH and Lanz-Mendoza H: The effect of nitric oxide and hydrogen peroxide in the activation of the systemic immune response of Anopheles albimanus infected with Plasmodium berghei. Dev Comp Immunol. 35:44–50. 2011. View Article : Google Scholar
10	Zimmermann N and Rothenberg ME: The arginine-arginase balance in asthma and lung inflammation. Eur J Pharmacol. 533:253–262. 2006. View Article : Google Scholar : PubMed/NCBI
11	Peranzoni E, Marigo I, Dolcetti L, Ugel S, Sonda N, Taschin E, Mantelli B, Bronte V and Zanovello P: Role of arginine metabolism in immunity and immunopathology. Immunobiology. 212:795–812. 2007. View Article : Google Scholar : PubMed/NCBI
12	Li Z, Zhao ZJ, Zhu XQ, Ren QS, Nie FF, Gao JM, Gao XJ, Yang TB, Zhou WL, Shen JL, et al: Differences in iNOS and arginase expression and activity in the macrophages of rats are responsible for the resistance against T. gondii infection. PLoS One. 7:e358342012. View Article : Google Scholar : PubMed/NCBI
13	Radi R: Nitric oxide, oxidants and protein tyrosine nitration. Proc Natl Acad Sci USA. 101:4003–4008. 2004. View Article : Google Scholar
14	Hillyer JF and Estévez-Lao TY: Nitric oxide is an essential component of the hemocyte-mediated mosquito immune response against bacteria. Dev Comp Immunol. 34:141–149. 2010. View Article : Google Scholar
15	Jung K, Gurnani A, Renukaradhya GJ and Saif LJ: Nitric oxide is elicited and inhibits viral replication in pigs infected with porcine respiratory coronavirus but not porcine reproductive and respiratory syndrome virus. Vet Immunol Immunopathol. 136:335–339. 2010. View Article : Google Scholar : PubMed/NCBI
16	Cloke T, Munder M, Bergin P, Herath S, Modolell M, Taylor G, Müller I and Kropf P: Phenotypic alteration of neutrophils in the blood of HIV seropositive patients. PLoS One. 8:e720342013. View Article : Google Scholar : PubMed/NCBI
17	Cloke TE, Garvey L, Choi BS, Abebe T, Hailu A, Hancock M, Kadolsky U, Bangham CR, Munder M, Müller I, et al: Increased level of arginase activity correlates with disease severity in HIV-seropositive patients. J Infect Dis. 202:374–385. 2010. View Article : Google Scholar : PubMed/NCBI
18	Cairoli E, Scott-Algara D, Pritsch O, Dighiero G and Cayota A: HIV-1 induced decrease of nitric oxide production and inducible nitric oxide synthase expression during in vivo and in vitro infection. Clin Immunol. 127:26–33. 2008. View Article : Google Scholar : PubMed/NCBI
19	Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Accessed November 9, 2015.
20	Tassone G and Fidler SJ: Separation and cryopreservation of lymphocytes from spleen and lymph node. Methods Mol Biol. 882:351–357. 2012. View Article : Google Scholar : PubMed/NCBI
21	Singh U and Owen JJ: Studies on subpopulations of foetal thymocytes separated on ficoll hypaque density gradients. Dev Comp Immunol. 3:543–556. 1979. View Article : Google Scholar : PubMed/NCBI
22	Matos LL, Stabenow E, Tavares MR, Ferraz AR, Capelozzi VL and Pinhal MA: Immunohistochemistry quantification by a digital computer-assisted method compared to semiquantitative analysis. Clinics (Sao Paulo). 61:417–424. 2006. View Article : Google Scholar
23	Koot M, Keet IP, Vos AH, de Goede RE, Roos MT, Coutinho RA, Miedema F, Schellekens PT and Tersmette M: Prognostic value of HIV-1 syncytium-inducing phenotype for rate of CD4+ cell depletion and progression to AIDS. Ann Intern Med. 118:681–688. 1993. View Article : Google Scholar : PubMed/NCBI
24	da Costa CM, de Freitas MR, Brazão V, dos Santos CD, Sala MA, do Prado Júnior JC and Abrahão AA: Does L-arginine availability during the early pregnancy alters the immune response of Trypanosoma cruzi infected and pregnant Wistar rats? Exp Parasitol. 142:59–66. 2014. View Article : Google Scholar : PubMed/NCBI
25	Willard-Mack CL: Normal structure, function, and histology of lymph nodes. Toxico Pathol. 34:409–424. 2006. View Article : Google Scholar
26	Gökmen SS, Aygit AC, Ayhan MS, Yorulmaz F and Gülen S: Significance of arginase and ornithine in malignant tumors of the human skin. J Lab Clin Med. 137:340–344. 2001. View Article : Google Scholar : PubMed/NCBI
27	Raber P, Ochoa AC and Rodriguez PC: Metabolism of L-arginine by myeloid-derived suppressor cells in cancer: Mechanisms of T cell suppression and therapeutic perspectives. Immunol Invest. 41:614–634. 2012. View Article : Google Scholar : PubMed/NCBI
28	Bansal V and Ochoa JB: Arginine availability, arginase and the immune response. Curr Opin Clin Nutr Metab Care. 6:223–228. 2003. View Article : Google Scholar : PubMed/NCBI
29	Ash DE, Cox JD and Christianson DW: Arginase: A binuclear manganese metalloenzyme. Met Ions Biol Sys. 37:407–428. 2000.
30	Jenkinson CP, Grody WW and Cederbaum SD: Comparative properties of arginases. Comp Biochem Physiol B Biochem Mol Biol. 114:107–132. 1996. View Article : Google Scholar : PubMed/NCBI
31	Wijnands KA, Hoeksema MA, Meesters DM, van den Akker NM, Molin DG, Briedé JJ, Ghosh M, Köhler SE, van Zandvoort MA, de Winther MP, et al: Arginase-1 deficiency regulates arginine concentrations and NOS2-mediated NO production during endotoxemia. PLoS One. 9:e861352014. View Article : Google Scholar : PubMed/NCBI
32	Takele Y, Abebe T, Weldegebreal T, Hailu A, Hailu W, Hurissa Z, Ali J, Diro E, Sisay Y, Cloke T, et al: Arginase activity in the blood of patients with visceral leishmaniasis and HIV infection. PLoS Negl Trop Dis. 7:e19772013. View Article : Google Scholar : PubMed/NCBI
33	McLarren KW, Cole AE, Weisser SB, Voglmaier NS, Conlin VS, Jacobson K, Popescu O, Boucher JL and Sly LM: SHIP-deficient mice develop spontaneous intestinal inflammation and arginase-dependent fibrosis. Am J Pathol. 179:180–188. 2011. View Article : Google Scholar : PubMed/NCBI
34	Endo M, Oyadomari S, Terasaki Y, Takeya M, Suga M, Mori M and Gotoh T: Induction of arginase I and II in bleomycin-induced fibrosis of mouse lung. Am J Physiol Lung Cell Mol Physiol. 285:L313–L321. 2013. View Article : Google Scholar
35	Barron L, Smith AM, El Kasmi KC, Qualls JE, Huang X, Cheever A, Borthwick LA, Wilson MS, Murray PJ and Wynn TA: Role of arginase 1 from myeloid cells in th2-dominated lung inflammation. PLoS One. 8:e619612013. View Article : Google Scholar : PubMed/NCBI
36	Bronte V and Zanovello P: Regulation of immune responses by L-arginine metabolism. Nat Rev Immunol. 5:641–654. 2005. View Article : Google Scholar : PubMed/NCBI
37	Érsek B, Molnár V, Balogh A, Matkó J, Cope AP, Buzás EI, Falus A and Nagy G: CD3 ζ -chain expression of human T lymphocytes is regulated by TNF via Src-like adaptor protein-dependent proteasomal degradation. J Immunol. 189:1602–1610. 2012. View Article : Google Scholar
38	Rodriguez PC, Quiceno DG and Ochoa AC: L-arginine availability regulates T-lymphocyte cell-cycle progression. Blood. 109:1568–1573. 2007. View Article : Google Scholar
39	Chaturvedi R, Asim M, Lewis ND, Algood HM, Cover TL, Kim PY and Wilson KT: L-arginine availability regulates inducible nitric oxide synthase-dependent host defense against Helicobacter pylori. Infect Immun. 75:4305–4315. 2007. View Article : Google Scholar : PubMed/NCBI
40	Wink DA, Hines HB, Cheng RY, Switzer CH, Flores-Santana W, Vitek MP, Ridnour LA and Colton CA: Nitric oxide and redox mechanisms in the immune response. J Leukoc Biol. 89:873–891. 2011. View Article : Google Scholar : PubMed/NCBI
41	Bogdan C: Nitric oxide and the immune response. Nat Immunol. 2:907–916. 2001. View Article : Google Scholar : PubMed/NCBI
42	Griffith OW and Stuehr DJ: Nitric oxide synthases: properties and catalytic mechanism. Annu Rev Physiol. 57:707–736. 1995. View Article : Google Scholar : PubMed/NCBI
43	Wu JX, Zhu HW, Chen X, Wei JL, Zhang XF and Xu MY: Inducible nitric oxide synthase inhibition reverses pulmonary arterial dysfunction in lung transplantation. Inflamm Res. 63:609–618. 2014. View Article : Google Scholar : PubMed/NCBI
44	Buttery LD, Springall DR, Chester AH, Evans TJ, Standfield EN, Parums DV, Yacoub MH and Polak JM: Inducible nitric oxide synthase is present within human atherosclerotic lesions and promotes the formation and activity of peroxynitrite. Lab Inves. 75:77–85. 1996.
45	Bronte V, Serafini P, Mazzoni A, Segal DM and Zanovello P: L-arginine metabolism in myeloid cells controls T-lymphocyte functions. Trends Immunol. 24:302–306. 2003. View Article : Google Scholar : PubMed/NCBI
46	Popovic PJ, Zeh HJ III and Ochoa JB: Arginine and immunity. J Nutr. 137(6 Suppl 2): S1681–S1686. 2007.
47	Steppan J, Nyhan D and Berkowitz DE: Development of novel arginase inhibitors for therapy of endothelial dysfunction. Front Immunol. 4:2782013. View Article : Google Scholar : PubMed/NCBI
48	Jung C, Quitter F, Lichtenauer M, Fritzenwanger M, Pfeil A, Shemyakin A, Franz M, Figulla HR, Pfeifer R and Pernow J: Increased arginase levels contribute to impaired perfusion after cardiopulmonary resuscitation. Eur J Clin Invest. 44:965–971. 2014. View Article : Google Scholar : PubMed/NCBI
49	Maarsingh H, Dekkers BG, Zuidhof AB, Bos IS, Menzen MH, Klein T, Flik G, Zaagsma J and Meurs H: Increased arginase activity contributes to airway remodelling in chronic allergic asthma. Eur Respir J. 38:318–328. 2011. View Article : Google Scholar : PubMed/NCBI
50	Horowitz S, Binion DG, Nelson VM, Kanaa Y, Javadi P, Lazarova Z, Andrekopoulos C, Kalyanaraman B, Otterson MF and Rafiee P: Increased arginase activity and endothelial dysfunction in human inflammatory bowel disease. Am J Physiol Gastrointest Liver Physiol. 292:G1323–G1336. 2007. View Article : Google Scholar : PubMed/NCBI
51	Kovamees O, Shemyakin A and Pernow J: Effect of arginase inhibition on ischemia-reperfusion injury in patients with coronary artery disease with and without diabetes mellitus. PLoS One. 9:e1032602014. View Article : Google Scholar : PubMed/NCBI
52	Hai Y, Edwards JE, Van Zandt MC, Hoffmann KF and Christianson DW: Crystal structure of Schistosoma mansoni arginase, a potential drug target for the treatment of schistosomiasis. Biochemistry. 53:4671–4684. 2014. View Article : Google Scholar : PubMed/NCBI
53	Wang S, Fang F, Jin WB, Wang X and Zheng DW: Assessment of serum arginase I as a type 2 diabetes mellitus diagnosis biomarker in patients. Exp Ther Med. 8:585–590. 2014.PubMed/NCBI