Regulatory T cells protect against hypoxia-induced pulmonary arterial hypertension in mice

Chu,Yanbiao; Xiangli,Xiaoying; Xiao,Wei

doi:10.3892/mmr.2014.3106

Regulatory T cells protect against hypoxia-induced pulmonary arterial hypertension in mice

Authors:
- Yanbiao Chu
- Xiaoying Xiangli
- Wei Xiao
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Affiliations: Department of Respiratory Medicine, Qilu Hospital, Shandong University, Jinan, Shandong 250012, P.R. China, Department of Surgery, Qilu Hospital, Shandong University, Jinan, Shandong 250012, P.R. China
Published online on: December 17, 2014 https://doi.org/10.3892/mmr.2014.3106
Pages: 3181-3187

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Abstract

Pulmonary arterial hypertension (PAH) is a life‑threatening disease characterized by the complex proliferation of the pulmonary vascular endothelium and progressive pulmonary vascular remodeling. CD4+CD25+ regulatory T cells (Tregs) have been the focus of numerous studies into PAH. The present study aimed to investigate the role and mechanisms of Tregs in hypoxia‑induced PAH. A total of 60 male mice were divided at random into three groups: Normoxia group, hypoxia control group and Tregs group. Measurements were obtained of the right ventricle systolic pressure (RVSP) and the Fulton's index; in addition, the mRNA and protein expression of pro‑inflammatory cytokines including monocyte chemotactic protein 1 (MCP‑1), interleukin (IL)‑1β and IL‑6, as well as the anti‑inflammatory cytokine IL‑10 in the lungs were determined by reverse transcription quantitative polymerase chain reaction and western blot analysis in vivo. Human pulmonary artery smooth muscle cells (HPASMCs) were cultured under hypoxic condition with or without Tregs for 48 h, and the proliferation rate and cell cycle of HPASMCs were determined. In addition, the protein levels of phosphorylated (p)‑Akt and p‑extracellular signal‑regulated kinase (ERK) were measured in HPASMCs in vitro. The results showed that Treg treatment significantly reduced the increased the hypoxia‑induced RVSP and Fulton's index, decreased pro‑inflammatory cytokine expression as well as enhanced IL‑10 levels in vivo. Furthermore, Treg treatment significantly reduced HPASMCs proliferation and the expression of cyclin D1, cyclin‑dependent kinase (CDK)4, p‑Akt and p‑ERK, as well as increased p27 expression in vitro. In conclusion, the results of the present study indicated that Tregs protected against hypoxia‑induced PAH in mice; the mechanisms of which may proceed via the suppression of the inflammatory response, as Tregs were found to enhance anti‑inflammatory cytokine levels, inhibit HPASMCs proliferation and regulate the cell cycle. These results therefore indicated that Tregs may be a potential novel target for the treatment of PAH.

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1	Gaine SP and Rubin LJ: Primary pulmonary hypertension. Lancet. 352:719–725. 1998. View Article : Google Scholar : PubMed/NCBI
2	Humbert M, Morrell NW, Archer SL, Stenmark KR, MacLean MR, Lang IM, Christman BW, Weir EK, Eickelberg O, Voelkel NF and Rabinovitch M: Cellular and molecular pathobiology of pulmonary arterial hypertension. J Am Coll Cardiol. 43(12 Suppl S): 13S–24S. 2004. View Article : Google Scholar : PubMed/NCBI
3	Owens GK, Kumar MS and Wamhoff BR: Molecular regulation of vascular smooth muscle cell differentiation in development and disease. Physiol Rev. 84:767–801. 2004. View Article : Google Scholar : PubMed/NCBI
4	Orlandi A, Bochaton-Piallat ML, Gabbiani G and Spagnoli LG: Aging, smooth muscle cells and vascular pathobiology: Implications for atherosclerosis. Atherosclerosis. 188:221–230. 2006. View Article : Google Scholar : PubMed/NCBI
5	Chen B, Calvert AE, Meng X and Nelin LD: Pharmacologic agents elevating cAMP prevent arginase II expression and proliferation of pulmonary artery smooth muscle cells. Am J Respir Cell Mol Biol. 47:218–226. 2012. View Article : Google Scholar : PubMed/NCBI
6	Stenmark KR, Fagan KA and Frid MG: Hypoxia-induced pulmonary vascular remodeling: Cellular and molecular mechanisms. Circ Res. 99:675–691. 2006. View Article : Google Scholar : PubMed/NCBI
7	Nicolls MR, Taraseviciene-Stewart L, Rai PR, Badesch DB and Voelkel NF: Autoimmunity and pulmonary hypertension: a perspective. Eur Respir J. 26:1110–1118. 2005. View Article : Google Scholar : PubMed/NCBI
8	Sakaguchi S: Naturally arising Foxp3-expressing CD25+CD4+ regulatory T cells in immunological tolerance to self and non-self. Nat Immunol. 6:345–352. 2005. View Article : Google Scholar : PubMed/NCBI
9	Meng X, Li W, Yang J, Zhang K, Qin W, An G, Gao F, Wang Y, Zhang C and Zhang Y: Regulatory T cells prevent plaque disruption in apolipoprotein E-knockout mice. Int J Cardiol. 168:2684–2692. 2013. View Article : Google Scholar : PubMed/NCBI
10	Ait-Oufella H, Wang Y, Herbin O, et al: Natural regulatory T cells limit angiotensin II-induced aneurysm formation and rupture in mice. Arterioscler Thromb Vasc Biol. 33:2374–2379. 2013. View Article : Google Scholar : PubMed/NCBI
11	Mor A, Planer D, Luboshits G, et al: Role of naturally occurring CD4+CD25+ regulatory T cells in experimental atherosclerosis. Arterioscler Thromb Vasc Biol. 27:893–900. 2007. View Article : Google Scholar : PubMed/NCBI
12	Yin M, Zhang J, Wang Y, et al: Deficient CD4+CD25+ T regulatory cell function in patients with abdominal aortic aneurysms. Arterioscler Thromb Vasc Biol. 30:1825–1831. 2010. View Article : Google Scholar : PubMed/NCBI
13	Guidi L, Felice C, Bonanno G, et al: FOXP3 T regulatory cell modifications in inflammatory bowel disease patients treated with anti-TNFα agents. Biomed Res Int. 2013:2863682013. View Article : Google Scholar
14	Oka M, Homma N, Taraseviciene-Stewart L, Morris KG, Kraskauskas D, Burns N, Voelkel NF and McMurtry IF: Rho kinase-mediated vasoconstriction is important in severe occlusive pulmonary arterial hypertension in rats. Circ Res. 100:923–929. 2007. View Article : Google Scholar : PubMed/NCBI
15	Lu X, Murphy TC, Nanes MS and Hart CM: PPAR{gamma} regulates hypoxia-induced nox4 expression in human pulmonary artery smooth muscle cells through NF-{kappa}B. Am J Physiol Lung Cell Mol Physiol. 299:L559–L566. 2010. View Article : Google Scholar : PubMed/NCBI
16	Kim JM, Rasmussen JP and Rudensky AY: Regulatory T cells prevent catastrophic autoimmunity throughout the lifespan of mice. Nat Immunol. 8:191–197. 2007. View Article : Google Scholar
17	Fang K, Fu W, Beardsley AR, Sun X, Lisanti MP and Liu J: Overexpression of caveolin-1 inhibits endothelial cell proliferation by arresting the cell cycle at G0/G1 phase. Cell Cycle. 6:199–204. 2007. View Article : Google Scholar : PubMed/NCBI
18	Kraaij MD, Savage ND, van der Kooij SW, Koekkoek K, Wang J, van den Berg JM, Ottenhoff TH, Kuijpers TW, Holmdahl R, van Kooten C and Gelderman KA: Induction of regulatory T cells by macrophages is dependent on production of reactive oxygen species. Proc Natl Acad Sci USA. 107:17686–17691. 2010. View Article : Google Scholar : PubMed/NCBI
19	Hassoun PM, Mouthon L, Barberà JA, et al: Inflammation, growth factors, and pulmonary vascular remodeling. J Am Coll Cardiol. 54(1 Suppl): S10–S19. 2009. View Article : Google Scholar : PubMed/NCBI
20	El Chami H and Hassoun PM: Inflammatory mechanisms in the pathogenesis of pulmonary arterial hypertension. Compr Physiol. 1:1929–1941. 2011.PubMed/NCBI
21	Schober A and Zernecke A: Chemokines in vascular remodeling. Thromb Haemost. 97:730–737. 2007.PubMed/NCBI
22	Itoh T, Nagaya N, Ishibashi-Ueda H, Kyotani S, Oya H, Sakamaki F, Kimura H and Nakanishi N: Increased plasma monocyte chemoattractant protein-1 level in idiopathic pulmonary arterial hypertension. Respirology. 11:158–163. 2006. View Article : Google Scholar : PubMed/NCBI
23	Steiner MK, Syrkina OL, Kolliputi N, Mark EJ, Hales CA and Waxman AB: Interleukin-6 overexpression induces pulmonary hypertension. Circ Res. 104:236–244. 2009. View Article : Google Scholar
24	Asadullah K, Sterry W and Volk HD: Interleukin-10 therapy - review of a new approach. Pharmacol Rev. 55:241–69. 2003. View Article : Google Scholar : PubMed/NCBI
25	Ito T, Okada T, Miyashita H, Nomoto T, Nonaka-Sarukawa M, Uchibori R, Maeda Y, Urabe M, Mizukami H, Kume A, Takahashi M, Ikeda U, Shimada K and Ozawa K: Interleukin-10 expression mediated by an adeno-associated virus vector prevents monocrotaline-induced pulmonary arterial hypertension in rats. Circ Res. 101:734–741. 2007. View Article : Google Scholar : PubMed/NCBI
26	Lavasani S, Dzhambazov B, Nouri M, et al: A novel probiotic mixture exerts a therapeutic effect on experimental autoimmune encephalomyelitis mediated by IL-10 producing regulatory T cells. PLoS One. 5:e90092010. View Article : Google Scholar : PubMed/NCBI
27	Owens GK: Regulation of differentiation of vascular smooth muscle cells. Physiol Rev. 75:487–517. 1995.PubMed/NCBI
28	Luo Y, Xu DQ, Dong HY, Zhang B, Liu Y, Niu W, Dong MQ and Li ZC: Tanshinone iia inhibits hypoxia-induced pulmonary artery smooth muscle cell proliferation via akt/skp2/p27-associated pathway. PLoS One. 8:e567742013. View Article : Google Scholar : PubMed/NCBI
29	Yu L, Quinn DA, Garg HG and Hales C: Gene expression of cyclin-dependent kinase inhibitors and effect of heparin on their expression in mice with hypoxia-induced pulmonary hypertension. Biochem Biophys Res Commun. 345:1565–1572. 2006. View Article : Google Scholar : PubMed/NCBI
30	Dong Y, Sui L, Sugimoto K, Tai Y and Tokuda M: Cyclin d1-cdk4 complex, a possible critical factor for cell proliferation and prognosis in laryngeal squamous cell carcinomas. Int J Cancer. 95:209–215. 2001. View Article : Google Scholar : PubMed/NCBI
31	Sakamoto K, Ohki K, Saito M, Nakahara T and Ishii K: Small molecule cyclin-dependent kinase inhibitors protect against neuronal cell death in the ischemic-reperfused rat retina. J Ocul Pharmacol Ther. 27:419–425. 2011. View Article : Google Scholar : PubMed/NCBI
32	Toyoshima H and Hunter T: P27, a novel inhibitor of g1 cyclin-cdk protein kinase activity, is related to p21. Cell. 78:67–74. 1994. View Article : Google Scholar : PubMed/NCBI