HIV‑1 downregulates the expression and phosphorylation of receptor tyrosine kinase by targeting the NF‑κB pathway

Feng,Tingting; Gan,Jianhe; Qin,Ailan; Huang,Xiaoping; Wu,Nanping; Hu,Hua; Yao,Hangping

doi:10.3892/mmr.2016.5487

HIV‑1 downregulates the expression and phosphorylation of receptor tyrosine kinase by targeting the NF‑κB pathway

Authors:
- Tingting Feng
- Jianhe Gan
- Ailan Qin
- Xiaoping Huang
- Nanping Wu
- Hua Hu
- Hangping Yao
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Affiliations: Department of Infectious Disease, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310003, P.R. China, Department of Neurology, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China
Published online on: July 8, 2016 https://doi.org/10.3892/mmr.2016.5487
Pages: 1947-1952
Copyright: © Feng et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Macrophages are major targets of human immunodeficiency virus (HIV) and can act as long‑term reservoirs of the virus. Chronic HIV‑1 infection is associated with dysregulated inflammation. Recepteur d'origine nantais (RON) is expressed in tissue resident macrophages and functions to maintain inflammatory homeostasis. The present study aimed to compare the expression of RON on HIV-positive and -negative participants, and to investigate the mechanism by which HIV‑1 influences the expression and function of RON in the JLTRG T cell line. The levels of RON and the RON ligand, macrophage‑stimulating protein (MSP), in the peripheral blood of HIV‑1-positive patients that were receiving (n=22) or not receiving highly active anti‑retroviral therapy (HAART) (n=82) and 37 healthy control participants were determined by enzyme‑linked immunosorbent assay. Expression of RON and MSP in the JLTRG T cell line was assessed by western blotting and the subcellular location was analyzed by fluorescence microscopy. JLTRG cells were co‑cultured with a cell line that stably expresses HIV, H9/HTLV‑IIIB, and alterations in the levels of RON and nuclear factor‑κB (NF‑κB) in JLTRG cells were assessed by western blotting. The expression of RON and MSP were significantly different in the serum of HIV‑1-positive patients that were receiving HAART compared with those not receiving HAART (P<0.05) and healthy control patients (P<0.01). RON was detected in JLTRG cells, and was shown to be downregulated by HIV‑1 infection. HIV‑1 infection of JLTRG cells also reduced NF‑κB phosphorylation. Thus, HIV‑1 was shown to downregulate the expression and phosphorylation of RON by targeting the NF‑κB pathway.

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1	Meltzer MS, Nakamura M, Hansen BD, Turpin JA, Kalter DC and Gendelman HE: Macrophages as susceptible targets for HIV infection, persistent viral reservoirs in tissue and key immunoregulatory cells that control levels of virus replication and extent of disease. AIDS Res Hum Retroviruses. 6:967–971. 1990.PubMed/NCBI
2	Balestra E, Perno CF, Aquaro S, Panti S, Bertoli A, Piacentini M, Forbici F, D'Arrigo R, Calió R and Garaci E: Macrophages: A crucial reservoir for human immunodeficiency virus in the body. J Biol Regul Homeost Agents. 15:272–276. 2001.PubMed/NCBI
3	Kedzierska K and Crowe SM: The role of monocytes and macrophages in the pathogenesis of HIV-1 infection. Curr Med Chem. 9:1893–1903. 2002. View Article : Google Scholar : PubMed/NCBI
4	Fantuzzi L, Belardelli F and Gessani S: Monocyte/macrophage-derived CC chemokines and their modulation by HIV-1 and cytokines: A complex network of interactions influencing viral replication and AIDS pathogenesis. J Leukoc Biol. 74:719–725. 2003. View Article : Google Scholar : PubMed/NCBI
5	Leonis MA, Thobe MN and Waltz SE: Ron-receptor tyrosine kinase in tumorigenesis and metastasis. Future Oncol. 3:441–448. 2007. View Article : Google Scholar : PubMed/NCBI
6	Correll PH, Morrison AC and Lutz MA: Receptor tyrosine kinases and the regulation of macrophage activation. J Leukoc Biol. 75:731–737. 2004. View Article : Google Scholar : PubMed/NCBI
7	Wang MH, Julian FM, Breathnach R, Godowski PJ, Takehara T, Yoshikawa W, Hagiya M and Leonard EJ: Macrophage stimulating protein (MSP) binds to its receptor via the MSP beta chain. J Biol Chem. 272:16999–17004. 1997. View Article : Google Scholar : PubMed/NCBI
8	Wang MH, Cox GW, Yoshimura T, Sheffler LA, Skeel A and Leonard EJ: Macrophage-stimulating protein inhibits induction of nitric oxide production by endotoxin- or cytokine-stimulated mouse macrophages. J Biol Chem. 269:14027–14031. 1994.PubMed/NCBI
9	Chen YQ, Fisher JH and Wang MH: Activation of the RON receptor tyrosine kinase inhibits inducible nitric oxide synthase (iNOS) expression by murine peritoneal exudate macrophages: Phosphatidylinositol-3 kinase is required for RON-mediated inhibition of iNOS expression. J Immunol. 161:4950–4959. 1998.PubMed/NCBI
10	Liu QP, Fruit K, Ward J and Correll PH: Negative regulation of macrophage activation in response to IFN-gamma and lipopolysaccharide by the STK/RON receptor tyrosine kinase. J Immunol. 163:6606–6613. 1999.PubMed/NCBI
11	Morrison AC, Wilson CB, Ray M and Correll PH: Macrophage-stimulating protein, the ligand for the stem cell-derived tyrosine kinase/RON receptor tyrosine kinase, inhibits IL-12 production by primary peritoneal macrophages stimulated with IFN-gamma and lipopolysaccharide. J Immunol. 172:1825–1832. 2004. View Article : Google Scholar : PubMed/NCBI
12	Morrison AC and Correll PH: Activation of the stem cell-derived tyrosine kinase/RON receptor tyrosine kinase by macrophage-stimulating protein results in the induction of arginase activity in murine peritoneal macrophages. J Immunol. 168:853–860. 2002. View Article : Google Scholar : PubMed/NCBI
13	Correll PH, Iwama A, Tondat S, Mayrhofer G, Suda T and Bernstein A: Deregulated inflammatory response in mice lacking the STK/RON receptor tyrosine kinase. Genes Funct. 1:69–83. 1997. View Article : Google Scholar : PubMed/NCBI
14	Leonis MA, Toney-Earley K, Degen SJ and Waltz SE: Deletion of the Ron receptor tyrosine kinase domain in mice provides protection from endotoxin-induced acute liver failure. Hepatology. 36:1053–1060. 2002. View Article : Google Scholar : PubMed/NCBI
15	Tsutsui S, Noorbakhsh F, Sullivan A, Henderson AJ, Warren K, Toney-Earley K, Waltz SE and Power C: RON-regulated innate immunity is protective in an animal model of multiple sclerosis. Ann Neurol. 57:883–895. 2005. View Article : Google Scholar : PubMed/NCBI
16	Klatt A, Zhang Z, Kalantari P, Hankey PA, Gilmour DS and Henderson AJ: The receptor tyrosine kinase RON represses HIV-1 transcription by targeting RNA polymerase II processivity. J Immunol. 180:1670–1677. 2008. View Article : Google Scholar : PubMed/NCBI
17	Lee ES, Kalantari P, Tsutsui Section S, Klatt A, Holden J, Correll PH, Power Section C and Henderson AJ: RON receptor tyrosine kinase, a negative regulator of inflammation, inhibits HIV-1 transcription in monocytes/macrophages and is decreased in brain tissue from patients with AIDS. J Immunol. 173:6864–6872. 2004. View Article : Google Scholar : PubMed/NCBI
18	Griffin GE, Leung K, Folks TM, Kunkel S and Nabel GJ: Activation of HIV gene expression during monocyte differentiation by induction of NF-kappa B. Nature. 339:70–73. 1989. View Article : Google Scholar : PubMed/NCBI
19	Harrich D, Garcia J, Wu F, Mitsuyasu R, Gonazalez J and Gaynor R: Role of SP1-binding domains in in vivo transcriptional regulation of the human immunodeficiency virus type 1 long terminal repeat. J Virol. 63:2585–2591. 1989.PubMed/NCBI
20	Henderson AJ, Connor RI and Calame KL: C/EBP activators are required for HIV-1 replication and proviral induction in monocytic cell lines. Immunity. 5:91–101. 1996. View Article : Google Scholar : PubMed/NCBI
21	Agbottah E, Deng L, Dannenberg LO, Pumfery A and Kashanchi F: Effect of SWI/SNF chromatin remodeling complex on HIV-1 Tat activated transcription. Retrovirology. 3:482006. View Article : Google Scholar : PubMed/NCBI
22	Mahmoudi T, Parra M, Vries RG, Kauder SE, Verrijzer CP, Ott M and Verdin E: The SWI/SNF chromatin-remodeling complex is a cofactor for Tat transactivation of the HIV promoter. J Biol Chem. 281:19960–19968. 2006. View Article : Google Scholar : PubMed/NCBI
23	Tréand C, du Chéné I, Brès V, Kiernan R, Benarous R, Benkirane M and Emiliani S: Requirement for SWI/SNF chromatin-remodeling complex in Tat-mediated activation of the HIV-1 promoter. Embo J. 25:1690–1699. 2006. View Article : Google Scholar : PubMed/NCBI
24	Kalantari P, Harandi OF, Hankey PA and Henderson AJ: HIV-1 Tat mediates degradation of RON receptor tyrosine kinase, a regulator of inflammation. J Immunol. 181:1548–1555. 2008. View Article : Google Scholar : PubMed/NCBI
25	Feng T, Shao X, Li J, et al: Human immunodeficiency virus (HIV)-1 Tat downregulates the phosphorylation of recepteur d'origine nantais (RON) receptor tyrosine kinase induced by macrophage-stimulating protein. African Journal of Biotechnology. 10:16610–16616. 2013.
26	Schneider E, Whitmore S, Glynn KM, Dominguez K, Mitsch A and McKenna MT; Centers for Disease Control and Prevention (CDC): Revised surveillance case definitions for HIV infection among adults, adolescents, and children aged <18 months and for HIV infection and AIDS among children aged 18 months to <13 years - United States, 2008. MMWR Recomm Rep. 57:1–12. 2008.PubMed/NCBI
27	Hargreaves N and Scano F: Guidelines for implementing collaborative TB and HIV programme activities. 2003
28	Lu Y, Yao HP and Wang MH: Multiple variants of the RON receptor tyrosine kinase: Biochemical properties, tumorigenic activities and potential drug targets. Cancer Lett. 257:157–164. 2007. View Article : Google Scholar : PubMed/NCBI
29	Lu Y, Yao HP and Wang MH: Significance of the entire C-terminus in biological activities mediated by the RON receptor tyrosine kinase and its oncogenic variant RON160. J Exp Clin Cancer Res. 27:552008. View Article : Google Scholar : PubMed/NCBI
30	Yao HP, Luo YL, Feng L, Cheng LF, Lu Y, Li W and Wang MH: Agonistic monoclonal antibodies potentiate tumorigenic and invasive activities of splicing variant of the RON receptor tyrosine kinase. Cancer Biol Ther. 5:1179–1186. 2006. View Article : Google Scholar : PubMed/NCBI
31	Guin S, Yao HP and Wang MH: RON receptor tyrosine kinase as a target for delivery of chemodrugs by antibody directed pathway for cancer cell cytotoxicity. Mol Pharm. 7:386–397. 2010. View Article : Google Scholar
32	Ochsenbauer-Jambor C, Jones J, Heil M, Zammit KP and Kutsch O: T-cell line for HIV drug screening using EGFP as a quantitative marker of HIV-1 replication. Biotechniques. 40:91–100. 2006. View Article : Google Scholar : PubMed/NCBI