Characterization of putative regulatory isoforms of porcine tumor necrosis factor receptor 2 in endothelial cells.
cell activation
cytokine receptors
endothelial cells
receptor isoforms
transplantation
Journal
Xenotransplantation
ISSN: 1399-3089
Titre abrégé: Xenotransplantation
Pays: Denmark
ID NLM: 9438793
Informations de publication
Date de publication:
11 2020
11 2020
Historique:
received:
06
04
2020
revised:
22
06
2020
accepted:
22
07
2020
pubmed:
13
8
2020
medline:
18
8
2021
entrez:
13
8
2020
Statut:
ppublish
Résumé
Tumor necrosis factor α (TNFα) and its receptors contribute to rejection of transplanted cells and organs. To elucidate how TNFα affects xenograft rejection, we previously cloned the cDNA of pig TNF-receptor 2 (pTNFR2) and found four isoforms: one comprising the full receptor with four cysteine-rich domains (CRD), a shorter variant (pTNFR2ΔE7-10) encoding for a soluble isoform, another lacking exon 4 (pTNFR2ΔE4) displaying only 3 CRD and poor ligand binding, and the smallest one generated by the two alternative splicings. All isoforms contained the pre-ligand assembly domain (PLAD) responsible for receptor trimerization. We now investigated their roles by structural, expression, and subcellular localization studies. Structural in silico analyses identified four amino acids potentially involved in TNFα binding and lacking in pTNFR2ΔE4. Quantitative RT-PCR determined regulated expression affecting the two pTNFR2 alternative splicings in cytokine-stimulated porcine aortic endothelial cells (PAEC). Particularly, human IL-1α and TNFα produced a strong mRNA upregulation of all isoforms, being the full receptor the predominant one. However, expression of pTNFR2 on PAEC did not correlate with mRNA and decreased after 24-hour exposure to IL-1α or TNFα. Notably, confocal microscopy confirmed the presence of pTNFR2 inside and on the plasma membrane, whereas pTNFR2ΔE4 located only intracellularly. Most interestingly, FRET analyses showed that membrane-bound isoforms pTNFR2 and pTNFR2ΔE4 colocalized intracellularly and associated through the PLAD. Our data show that pTNFR2ΔE4 bind and may retain the full receptor intracellularly. This mechanism has not been described in other species and represents a particularity that may affect the pathophysiology of pig xenografts.
Substances chimiques
Protein Isoforms
0
Receptors, Tumor Necrosis Factor, Type II
0
Tumor Necrosis Factor-alpha
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e12635Informations de copyright
© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
Références
Costa C, Casinghino SR, Fodor WL. Characterization of porcine tumor necrosis factor receptor 2: implications for xenotransplantation. Transplant Proc. 2007;39:2443-2446.
Uribe-Herranz M, Casinghino SR, Bosch-Presegué L, Fodor WL, Costa C. Identification of soluble and membrane-bound isoforms of porcine tumor necrosis factor receptor 2. Xenotransplantation. 2011;18:131-146.
Bradley JR. TNF-mediated inflammatory disease. J Pathol. 2008;214:149-160.
Faustman DL, Davis M. TNF Receptor 2 and disease: autoimmunity and regenerative medicine. Front Immunol. 2013;4:478.
Luo D, Luo Y, He Y, et al. Differential functions of tumor necrosis factor receptor 1 and 2 signaling in ischemia-mediated arteriogenesis and angiogenesis. Am J Pathol. 2006;169:1886-1898.
Yang S, Wang Y, Mei K, et al. Tumor necrosis factor receptor 2 (TNFR2)·interleukin-17 receptor D (IL-17RD) heteromerization reveals a novel mechanism for NF-κB activation. J Biol Chem. 2015;290:861-871.
Nübel T, Schmitt S, Kaina B, Fritz G. Lovastatin stimulates p75 TNF receptor (TNFR2) expression in primary human endothelial cells. Int J Mol Med. 2005;16:1139-1145.
Bodmer J, Schneider P, Tschopp J. The molecular architecture of the TNF superfamily. Trends Biochem Sci. 2002;27:19-26.
Chan FK, Chun HJ, Zheng L, Siegel RM, Bui KL, Lenardo MJ. A domain in TNF receptors that mediates ligand-independent receptor assembly and signaling. Science. 2000;288:2351-2354.
Mukai Y, Nakamura T, Yoshikawa M, et al. Solution of the structure of the TNF-TNFR2 complex. Sci Signal. 2010;3:ra83.
Grell M, Douni E, Wajant H, et al. The transmembrane form of tumor necrosis factor is the prime activating ligand of the 80 kDa tumor necrosis factor receptor. Cell. 1995;83:793-802.
Grell M, Wajant H, Zimmermann G, Scheurich P. The type 1 receptor (CD120a) is the high-affinity receptor for soluble tumor necrosis factor. Proc Natl Acad Sci USA. 1998;95:570-575.
Rauert H, Wicovsky A, Müller N, et al. Membrane tumor necrosis factor (TNF) induces p100 processing via TNF receptor-2 (TNFR2). J Biol Chem. 2010;285:7394-7404.
Al-Lamki RS, Wang J, Vandenabeele P, et al. TNFR1- and TNFR2-mediated signaling pathways in human kidney are cell type-specific and differentially contribute to renal injury. FASEB J. 2005;19:1637-1645.
Wilson NS, Dixit V, Ashkenazi A. Death receptor signal transducers: nodes of coordination in immune signaling networks. Nat Immunol. 2009;10:348-355.
Weiss T, Grell M, Siemienski K, et al. TNFR80-dependent enhancement of TNFR60-induced cell death is mediated by TNFR-associated factor 2 and is specific for TNFR60. J Immunol. 1998;161:3136-3142.
Li X, Yang Y, Ashwell JD. TNF-RII and c-IAP1 mediate ubiquitination and degradation of TRAF2. Nature. 2002;416:345-347.
Lainez B, Fernandez-Real JM, Romero X, et al. Identification and characterization of a novel spliced variant that encodes human soluble tumor necrosis factor receptor 2. Int Immunol. 2004;16:169-177.
Kim EY, Priatel JJ, Teh S, Teh H. TNF receptor type 2 (p75) functions as a costimulator for antigen-driven T cell responses in vivo. J Immunol. 2006;176:1026-1035.
Chen X, Oppenheim JJ. TNF-alpha: an activator of CD4+FoxP3+TNFR2+ regulatory T cells. Curr Dir Autoimmun. 2010;11:119-134.
Hu X, Li B, Li X, et al. Transmembrane TNF-α promotes suppressive activities of myeloid-derived suppressor cells via TNFR2. J Immunol. 2014;192:1320-1331.
Gao H, Danzi MC, Choi CS, et al. Opposing functions of microglial and macrophagic TNFR2 in the pathogenesis of experimental autoimmune encephalomyelitis. Cell Rep. 2017;18:198-212.
Chandrasekharan UM, Siemionow M, Unsal M, et al. Tumor necrosis factor alpha (TNF-alpha) receptor-II is required for TNF-alpha-induced leukocyte-endothelial interaction in vivo. Blood. 2007;109:1938-1944.
Pircher J, Merkle M, Wörnle M, et al. Prothrombotic effects of tumor necrosis factor alpha in vivo are amplified by the absence of TNF-alpha receptor subtype 1 and require TNF-alpha receptor subtype 2. Arthritis Res Ther. 2012;14:R225.
Venkatesh D, Ernandez T, Rosetti F, et al. Endothelial TNF receptor 2 induces IRF1 transcription factor-dependent interferon-β autocrine signaling to promote monocyte recruitment. Immunity. 2013;38:1025-1037.
Pan S, An P, Zhang R, He X, Yin G, Min W. Etk/Bmx as a tumor necrosis factor receptor type 2-specific kinase: role in endothelial cell migration and angiogenesis. Mol Cell Biol. 2002;22:7512-7523.
Zhang L, Sivashanmugam P, Wu JH, et al. Tumor necrosis factor receptor-2 signaling attenuates vein graft neointima formation by promoting endothelial recovery. Arterioscler Thromb Vasc Biol. 2008;28:284-289.
Lin Y, Vandeputte M, Waer M. Contribution of activated macrophages to the process of delayed xenograft rejection. Transplantation. 1997;64:1677-1683.
Lin H, Gastman BR, Wei RQ, Kunkel SL, Gordon D, Bolling SF. Phase-directed therapy and cardiac xenograft survival. J Surg Res. 1997;72:84-88.
Carel JC, Sheehan KC, Schreiber RD, Lacy PE. Prevention of rejection of transforming growth factor beta-treated rat-to-mouse islet xenografts by monoclonal antibody to tumor necrosis factor. Transplantation. 1993;55:456-458.
Kirkiles-Smith NC, Tereb DA, Kim RW, et al. Human TNF can induce nonspecific inflammatory and human immune-mediated microvascular injury of pig skin xenografts in immunodeficient mouse hosts. J Immunol. 2000;164:6601-6609.
Zhao Y, Cooper DKC, Wang H, et al. Potential pathological role of pro-inflammatory cytokines (IL-6, TNF-α, and IL-17) in xenotransplantation. Xenotransplantation. 2019;26:e12502.
Costa C, Bell NK, Stabel TJ, Fodor WL. Use of porcine tumor necrosis factor receptor 1-Ig fusion protein to prolong xenograft survival. Xenotransplantation. 2004;11:491-502.
Gao H, Liu L, Zhao Y, et al. Human IL-6, IL-17, IL-1β, and TNF-α differently regulate the expression of pro-inflammatory related genes, tissue factor, and swine leukocyte antigen class I in porcine aortic endothelial cells. Xenotransplantation. 2017;24(2):e12291.
Gao H, Cao M, Chen P, et al. TNF-α promotes human antibody-mediated complement-dependent cytotoxicity of porcine endothelial cells through downregulating P38-mediated Occludin expression. Cell Commun Signal. 2019;17:75.
Gao H, Zhang Q, Chen J, et al. Porcine IL-6, IL-1β, and TNF-α regulate the expression of pro-inflammatory-related genes and tissue factor in human umbilical vein endothelial cells. Xenotransplantation. 2018;25:e12408.
Diller R, Winde G, Kötting S, Senninger N, Dietl K, Spiegel H. sTNF-RII: is it useful for the early diagnosis of rejection and for prognosis after renal transplantation? Transpl Int. 2002;15:335-340.
Al-Lamki RS, Brookes AP, Wang J, et al. TNF receptors differentially signal and are differentially expressed and regulated in the human heart. Am J Transplant. 2009;9:2679-2696.
Zhang Y, Zhao J, Lau WB, et al. Tumor necrosis factor-α and lymphotoxin-α mediate myocardial ischemic injury via TNF receptor 1, but are cardioprotective when activating TNF receptor 2. PLoS One. 2013;8:e60227.
Madsen PM, Motti D, Karmally S, et al. Oligodendroglial TNFR2 mediates membrane TNF-dependent repair in experimental autoimmune encephalomyelitis by promoting oligodendrocyte differentiation and remyelination. J Neurosci. 2016;36:5128-5143.
Bradley JR, Thiru S, Pober JS. Disparate localization of 55-kd and 75-kd tumor necrosis factor receptors in human endothelial cells. Am J Pathol. 1995;146:27-32.
Scherübl C, Schneider-Brachert W, Schütze S, Hehlgans T, Männel DN. Colocalization of endogenous TNF with a functional intracellular splice form of human TNF receptor type 2. J Inflamm. 2005;2:7.
Seitz C, Muller P, Krieg RC, Mannel DN, Hehlgans T. A novel p75TNF receptor isoform mediating NFkappa B activation. J Biol Chem. 2001;276:19390-19395.
Hauser A, Hehlgans T, Männel DN. Characterization of TNF receptor type 2 isoform in the mouse. Mol Immunol. 2007;44:3563-3570.
Clancy L, Mruk K, Archer K, et al. Preligand assembly domain-mediated ligand-independent association between TRAIL receptor 4 (TR4) and TR2 regulates TRAIL-induced apoptosis. Proc Natl Acad Sci USA. 2005;102:18099-18104.
Cho B, Koo OJ, Hwang JI, et al. Generation of soluble human tumor necrosis factor-α receptor 1-Fc transgenic pig. Transplantation. 2011;92:139-147.