Transforming Growth Factor Beta-Induced Is Essential for Endotoxin Tolerance Induced by a Low Dose of Lipopolysaccharide in Human Peripheral Blood Mononuclear Cells
Abstract
Our prior study found that transforming growth factor beta-induced (TGFBI) is an important negative regulator in TLR-induced inflammation. However, whether TGFBI may affect inflammation during lipopolysaccharide (LPS)-induced endotoxin tolerance (ET) is still unclear.This study aimed to investigate whether TGFBI was involved in the mechanisms of ET in human through dampening nuclear factor-kappa B (NF-κB) mediated pathway. ET models of isolated healthy volunteers peripheral blood mononuclear cells (PBMCs) were established by pretreating with a low dose of LPS to observe the changes of TGFBI expression during ET induction, compared with ten healthy controls. Moreover, a vector-based short hairpin RNA expression system was used to specifically inhibit TGFBI expression to further explore its role in ET induction. The expression was analyzed by reverse transcription-polymerase chain reaction (RT-PCR) and Western blotting. The responses to LPS were determined by the activation of NF-κB, the production of tumor necrosis factor-α (TNF-α) and Nitric Oxide (NO), which were analysed by enzyme-linked immuno sorbent assay (ELISA).The results showed that TGFBI expression in the ET group obviously increased; ET also led to a hyporesponse of PBMCs to LPS with less activation of NF-κB, less production of TNF-α and NO, as well as more expression of TGFBI than those of non-ET group. Moreover, the inhibitory effect was partly refracted in plasmid TGFBI short hairpin RNA (pTGFBI-shRNA) transfected PBMCs. Meanwhile, the absence of TGFBI caused abnormal enhancement of inflammatory cytokine production and it was involved in ET induction through dampening NF-κB mediated pathway.Therefore, TGFBI may be a new target for the clinical treatment of inflammatory disorders.
1. Murad S. Toll-like receptor 4 in inflammation and angiogenesis: a double-edged sword. Front Immunol 2014; 5:313.
2. Foster SL, Medzhitov R. Gene-specific control of the TLR induced inflammatory response. Clin Immunol 2009;130(1):7-15.
3. Gooshe M, Aleyasin AR, Abdolghaffari AH, Rezaei N.Toll like receptors: a new hope on the horizon to treat multiple sclerosis. Expert Rev Clin Immunol 2014;10(10):1277-9.
4. Kumar S, Ingle H, Prasad DV, Kumar H. Recognition of bacterial infection by innate immune sensors. Crit Rev Microbiol 2013; 39(3):229-46.
5. Paludo FJ, Bristot IJ, Alho CS, Gelain DP, Moreira JC.Effects of 47C allele (rs4880) of the SOD2 gene in the production of intracellular reactive species in peripheral blood mononuclear cells with and without lipopolysaccharides induction. Free Radic Res 2014;48(2):190-9.
6. Liew FY, Xu D, Brint EK, O'Neill LA. Negative regulation of toll-like receptor-mediated immune responses. Nat Rev Immunol 2005; 5(6):446-58.
7. Shibolet O, Podolsky DK. TLRs in the gut. IV. Negative regulation of Toll-like receptors and intestinal homeostasis: addition by subtraction. Am J Physiol Gastrointest Liver Physiol 2007; 292(6):G1469-73.
8. Medvedev AE, Sabroe I, Hasday JD, Vogel SN. Tolerance to microbial TLR ligands: Molecular mechanisms and relevance to disease. J Endotoxin Res 2006; 12(3):133-50.
9. Torraca V, Masud S, Spaink HP, Meijer AH. Macrophage- pathogen interactions in infectious diseases: new therapeutic insights from the zebrafish host model. Dis Model Mech 2014; 7(7):785-97.
10. Skonier J, Neubauer M, Madisen L, Bennett K, Plowman GD, Purchio AF. cDNA cloning and sequence analysis of beta ig-h3, a novel gene induced in a human adenocarcinoma cell line after treatment with transforming growth factor-beta. DNA Cell Biol 1992;11(7):511-22.
11. Yang Y, Sun H, Mo X, Liu Y, Jia H, Li X, et al. Prediction of novel genes associated with negative regulators of toll- like receptors-induced inflammation based on endotoxin tolerance. Inflammation 2012; 35(6):1889-99.
12. Liu C, Li B, Cheng Y, Lin J, Hao J, Zhang S, et al. MiR-21 plays an important role in radiation induced carcinogenesis in BALB/c mice by directly targeting the tumor suppressor gene Big-h3. Int J Biol Sci 2011;7(3):347-63.
13. Schmitt-Bernard CF, Pouliquen Y, Argilès A. BIG-H3 protein: mutation of codon 124 and corneal amyloidosis. J Fr Ophtalmol 2004; 27(5):510-22.
14. Inoue T, Watanabe H, Yamamoto S, Maeda N, Inoue Y,Shimomura Y, et al. Recurrence of corneal dystrophy resulting from an R124H Big-h3 mutation after phototherapeutic keratectomy. Cornea 2002; 21(6):570-3.
15. Inoue T, Watanabe H, Yamamoto S, Inoue Y, Okada M,Hori Y, et al. Different recurrence patterns after phototherapeutic keratectomy in the corneal dystrophy resulting from homozygous and heterozygous R124H BIG-H3 mutation. Am J Ophthalmol 2001; 132(2):255-7.
16. Livshits L, Pampukha VM, Tereshchenko FA, Drozhyna
GI. Gene symbol: TGFBI. Disease: Corneal dystrophy, lattice type. Hum Genet 2008; 124(3):296-7.
17. Thapa N, Lee BH, Kim IS. TGFBIp/betaig-h3 protein: a versatile matrix molecule induced by TGF-beta. Int J Biochem Cell Biol 2007; 39(12):2183-94.
18. Cho JH, Hur IK, Kim CD, Park SH, Ryu HM, Yook JM, et al. Impact of systemic and local peritoneal inflammation on peritoneal solute transport rate in new peritoneal dialysis patients: a 1-year prospective study. Nephrol Dial Transplant 2010; 25(6):1964-73.
19. Cha J, Kwak T, Butmarc J, Kim TA, Yufit T, Carson P, et al. Fibroblasts from non-healing human chronic wounds show decreased expression of beta ig-h3, a TGF-beta inducible protein. J Dermatol Sci 2008; 50(1):15-23.
20. Lauden L, Siewiera J, Boukouaci W, Ramgolam K, Mourah S, Lebbe C, et al. TGF-β-induced (TGFBI) protein in melanoma: a signature of high metastatic potential. J Invest Dermatol 2014;134(6):1675- 85.
21. Kitahama S, Gibson MA, Hatzinikolas G, Hay S, Kuliwaba JL, Evdokiou A, et al. Expression of fibrillins and other microfibril- associated proteins in human bone and osteoblast-like cells. Bone 2000; 27(1):61-7.
22. Hilliard LM, Russo LM, Comper WD. Hypertension- mediated albuminuria is associated with reduced lysosomal activity in the kidney and the heart. Am J Nephrol 2009; 29(5):454-64.
23. 1 . del Fresno C, García-Rio F, Gómez-Piña V, Soares-Schanoski A, Fernández-Ruíz I, Jurado T, et al. Potent phagocytic activity with impaired antigen presentation identifying lipopolysaccharide-tolerant human monocytes: demonstration in isolated monocytes from cystic fibrosis patients. J Immunol 2009; 182(10):6494-507.
24. Tanaka Y, Kawanishi N, Shiva D, Tsutsumi N, Uchida M, Kitamura H, et al. Exhaustive exercise reduces tumor necrosis factor-alpha production in response to lipopolysaccharide in mice. Neuroimmunomodulation 2010; 17(4):279-86.
25. Wong HR, Odoms K, Sakthivel B. Divergence of canonical danger signals: the genome-level expression patterns of human mononuclear cells subjected to heat shock or lipopolysaccharide. BMC Immunol 2008; 9:24.
26. McDonald B, Jenne CN, Zhuo L, Kimata K, Kubes P.Kupffer cells and activation of endothelial TLR4 coordinate neutrophil adhesion within liver sinusoids during endotoxemia. Am J Physiol Gastrointest Liver Physiol 2013; 305(11):G797-806.
27. Copin R, Vitry MA, Hanot Mambres D, Machelart A, De Trez C, Vanderwinden JM, et al. In situ microscopy analysis reveals local innate immune response developed around Brucella infected cells in resistant and susceptible mice. PLoS Pathog 2012; 8(3):e1002575.
28. Nam EJ, Sa KH, You DW, Cho JH, Seo JS, Han SW, et al.Up-regulated transforming growth factor betainducible gene h3 in rheumatoid arthritis mediates adhesion and migration of synoviocytes through alphavbeta3 integrin: Regulation by cytokines. Arthritis Rheum 2006;54(9):2734-44.
29. O'Brien ER, Bennett KL, Garvin MR, Zderic TW, Hinohara T, Simpson JB, et al. Beta ig-h3, a transforming growth factor-beta-inducible gene, is overexpressed in atherosclerotic and restenotic human vascular lesions. Arterioscler Thromb Vasc Biol 1996; 16(4):576-84.
30. Li C, Lim SW, Choi BS, Lee SH, Cha JH, Kim IS, et al.Inhibitory effect of pervastatin on transforming growth factor beta1-inducible gene h3 expression in a rat model of chronic cyclosporine nephropathy. Am J Nephrol 2005;25(6):611-20.
31. Yun SJ, Kim MO, Kim SO, Park J, Kwon YK, Kim IS, et al. Induction of TGF-beta-inducible gene-h3 (betaig-h3) by TGF-beta1 in astrocytes: Implications for astrocytes response to brain injury. Brain Res Mol Brain Res 2002;107(1):57-64.
32. Kim JE, Kim SJ, Jeong HW, Lee BH, Choi JY, Park RW, Park JY, et al. RGD peptides released from beta ig-h3, a TGF-beta-induced celladhesive molecule,mediate apoptosis. Oncogene 2003; 22(13):2045-53.
33. Tang J, Wu YM, Zhao P, Jiang JL, Chen ZN. Betaig-h3 interacts with alpha3beta1 integrin to promote adhesion and migration of human hepatoma cells. Exp Biol Med (Maywood) 2009; 234(1):35-9.
34. Li C, Lim SW, Choi BS, Lee SH, Cha JH, Kim IS, et al.Inhibitory effect of pravastatin on transforming growth factor beta1-inducible gene h3 expression in a rat model of chronic cyclosporine nephropathy. Am J Nephrol 2005;25(6):611-20.
35. Nam EJ, Sa KH, You DW, Cho JH, Seo JS, Han SW, et al.Up-regulated transforming growth factorbinducible gene h3 in rheumatoid arthritis mediates adhesion and migration of synoviocytes through alpha v beta3 integrin: regulation by cytokines. Arthritis Rheum 2006; 54(9):2734-44.
36. Lorda-Diez CI, Montero JA, Diaz-Mendoza MJ, Garcia- Porrero JA, Hurle JM. βig-h3 potentiates the profibrogenic effect of TGFβ signaling on connective tissue progenitor cells through the negative regulation of master chondrogenic genes. Tissue Eng Part A 2013;19(3-4):448-57.
37. Wen G, Partridge MA, Li B, Hong M, Liao W, Cheng SK, et al. TGFBI expression reduces in vitro and in vivo metastatic potential of lung and breast tumor cells. Cancer Lett 2011; 308(1):23-32.
38. Ha SW, Bae JS, Yeo HJ, Lee SH, Choi JY, Sohn YK, et al.TGF-beta-induced proteinbig-h3 is upregulated by high glucose in vascular smooth muscle cells. J Cell Biochem 2003; 88(4):774-82.
39. Li B, Wen G, Zhao Y, Tong J, Hei TK. The role of TGFBI in mesothelioma and breast cancer: association with tumor suppression. BMC Cancer 2012; 12:239.
40. Adamik J, Wang KZ, Unlu S, Su AJ, Tannahill GM, Galson DL, et al. Distinct mechanisms for induction and tolerance regulate the immediate early genes encoding interleukin 1β and tumor necrosis factor α. PLoS One 2013; 8(8):e70622.
41. Fairfax BP, Davenport EE, Makino S, Hill AV, Vannberg FO, Knight JC. A common haplotype of the TNF receptor 2 gene modulates endotoxin tolerance. J Immunol 2011;186(5):3058-65.
42. Hayden MS, Ghosh S. Shared principles in NF-Κbm signaling. Cell 132(3):344-62.
43. Jeon ST, Kim WJ, Lee SM, Lee MY, Park SB, Lee SH, et al. Reverse signaling through BAFF differentially regulates the expression of inflammatory mediators and cytoskeletal movements in THP-1 cells. Immunol Cell Biol 2010; 88(2):148-56.
44. Wu Q, van Dyk LF, Jiang D, Dakhama A, Li L, White SR, et al. Interleukin-1 receptor-associated kinase M (IRAK- M) promotes human rhinovirus infection in lung epithelial cells via the autophagic pathway. Virology 2013;446(1-2):199-206.
45. Del-Fresno C, Soler-Rangel L, Soares-Schanoski A, Gómez-Piña V, González- León MC, Gómez-García L, et al. Inflammatory responses associated with acute coronary syndrome up-regulate IRAK-M and induce endotoxin tolerance in circulating monocytes. Endotoxin Res 2007; 13(1):39-52.
46. Morris M, Li L. Molecular mechanisms and pathological consequences of endotoxin tolerance and priming. Arch Immunol Ther Exp (Warsz) 2012; 60(1):13-8.
47. Matsushita H, Ohta S, Shiraishi H, Suzuki S, Arima K, Toda S, Tanaka H, Nagai H, Kimoto M, Inokuchi A, Izuhara K. (2010) Endotoxin tolerance attenuates airway allergic inflammation in model mice by suppression of the T-cell stimulatory effect of dendritic cells. Int Immunol 2010; 22:739-47.
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Issue | Vol 14, No 3 (2015) | |
Section | Original Article(s) | |
Keywords | ||
Endotoxin tolerance Lipopolysaccharide PBMCs TGFBI |
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