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Published in: Journal of Clinical Immunology 2/2009

01-03-2009

Clinical Significance of Serum HMGB-1 and sRAGE Levels in Systemic Sclerosis: Association with Disease Severity

Authors: Ayumi Yoshizaki, Kazuhiro Komura, Yohei Iwata, Fumihide Ogawa, Toshihide Hara, Eiji Muroi, Motoi Takenaka, Kazuhiro Shimizu, Minoru Hasegawa, Manabu Fujimoto, Shinichi Sato

Published in: Journal of Clinical Immunology | Issue 2/2009

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Abstract

Introduction

The high mobility group box 1 protein (HMGB-1)/advanced glycation end products (RAGE) system is recently shown to play an important part in immune/inflammatory disorders. However, the association of this system in systemic sclerosis (SSc) remains unknown.

Materials and Methods

To determine clinical association of serum levels of HMGB-1 and soluble RAGE (sRAGE) in patients with SSc, sera from 70 patients with SSc and 25 healthy controls were examined by enzyme-linked immunosorbent assay. Sera from tight-skin mice and bleomycin-induced scleroderma mice, animal models for SSc, were also examined. Skin HMGB-1 and RAGE expression was assessed by immunohistochemistry.

Results and Discussion

Serum HMGB-1 and sRAGE levels in SSc were higher than those in controls. Similarly, HMGB-1 and sRAGE levels in animal SSc models were higher than those in control mice. SSc patients with elevated HMGB-1 and sRAGE levels had more frequent involvement of several organs and immunological abnormalities compared to those with normal levels. Furthermore, HMGB-1 and sRAGE levels correlated positively with modified Rodnan total skin thickness score and negatively with pulmonary function test.

Conclusions

HMGB-1 and sRAGE expression in the sclerotic skin was more intense than normal skin. These results suggest that elevated serum HMGB-1 and sRAGE levels are associated with the disease severity and immunological abnormalities in SSc.
Literature
2.
go back to reference La Montagna G, D’Angelo S, Valentini G. Cross-sectional evaluation of ykl-40 serum concentrations in patients with systemic sclerosis. Relationship with clinical and serological aspects of disease. J Rheumatol. 2003;30:2147–51.PubMed La Montagna G, D’Angelo S, Valentini G. Cross-sectional evaluation of ykl-40 serum concentrations in patients with systemic sclerosis. Relationship with clinical and serological aspects of disease. J Rheumatol. 2003;30:2147–51.PubMed
3.
go back to reference Szegedi A, Czirjak L, Unkeless JC, Boros P. Serum cytokine and anti-fc gamma r autoantibody measurements in patients with systemic sclerosis. Acta Derm Venereol. 1996;76:21–3.PubMed Szegedi A, Czirjak L, Unkeless JC, Boros P. Serum cytokine and anti-fc gamma r autoantibody measurements in patients with systemic sclerosis. Acta Derm Venereol. 1996;76:21–3.PubMed
10.
go back to reference Bartling B, Fuchs C, Silber RE, Simm A. Fibroblasts mediate induction of high mobility group box protein 1 in lung epithelial cancer cells by diffusible factors. Int J Mol Med. 2007;20:217–24.PubMed Bartling B, Fuchs C, Silber RE, Simm A. Fibroblasts mediate induction of high mobility group box protein 1 in lung epithelial cancer cells by diffusible factors. Int J Mol Med. 2007;20:217–24.PubMed
12.
go back to reference Tian J, Avalos AM, Mao SY, Chen B, Senthil K, Wu H, et al. Toll-like receptor 9-dependent activation by DNA-containing immune complexes is mediated by HMGB1 and rage. Nat Immunol. 2007;8:487–96. doi:10.1038/ni1457.PubMedCrossRef Tian J, Avalos AM, Mao SY, Chen B, Senthil K, Wu H, et al. Toll-like receptor 9-dependent activation by DNA-containing immune complexes is mediated by HMGB1 and rage. Nat Immunol. 2007;8:487–96. doi:10.​1038/​ni1457.PubMedCrossRef
14.
go back to reference Malherbe P, Richards JG, Gaillard H, Thompson A, Diener C, Schuler A, et al. cDNA cloning of a novel secreted isoform of the human receptor for advanced glycation end products and characterization of cells co-expressing cell-surface scavenger receptors and Swedish mutant amyloid precursor protein. Brain Res Mol Brain Res. 1999;71:159–70. doi:10.1016/S0169-328X(99)00174-6.PubMedCrossRef Malherbe P, Richards JG, Gaillard H, Thompson A, Diener C, Schuler A, et al. cDNA cloning of a novel secreted isoform of the human receptor for advanced glycation end products and characterization of cells co-expressing cell-surface scavenger receptors and Swedish mutant amyloid precursor protein. Brain Res Mol Brain Res. 1999;71:159–70. doi:10.​1016/​S0169-328X(99)00174-6.PubMedCrossRef
15.
go back to reference Yonekura H, Yamamoto Y, Sakurai S, Petrova RG, Abedin MJ, Li H, et al. Novel splice variants of the receptor for advanced glycation end-products expressed in human vascular endothelial cells and pericytes, and their putative roles in diabetes-induced vascular injury. Biochem J. 2003;370:1097–109. doi:10.1042/BJ20021371.PubMedCrossRef Yonekura H, Yamamoto Y, Sakurai S, Petrova RG, Abedin MJ, Li H, et al. Novel splice variants of the receptor for advanced glycation end-products expressed in human vascular endothelial cells and pericytes, and their putative roles in diabetes-induced vascular injury. Biochem J. 2003;370:1097–109. doi:10.​1042/​BJ20021371.PubMedCrossRef
16.
go back to reference Park IH, Yeon SI, Youn JH, Choi JE, Sasaki N, Choi IH, et al. Expression of a novel secreted splice variant of the receptor for advanced glycation end products (rage) in human brain astrocytes and peripheral blood mononuclear cells. Mol Immunol. 2004;40:1203–11. doi:10.1016/j.molimm.2003.11.027.PubMedCrossRef Park IH, Yeon SI, Youn JH, Choi JE, Sasaki N, Choi IH, et al. Expression of a novel secreted splice variant of the receptor for advanced glycation end products (rage) in human brain astrocytes and peripheral blood mononuclear cells. Mol Immunol. 2004;40:1203–11. doi:10.​1016/​j.​molimm.​2003.​11.​027.PubMedCrossRef
18.
go back to reference Ueno H, Matsuda T, Hashimoto S, Amaya F, Kitamura Y, Tanaka M, et al. Contributions of high mobility group box protein in experimental and clinical acute lung injury. Am J Respir Crit Care Med. 2004;170:1310–6. doi:10.1164/rccm.200402-188OC.PubMedCrossRef Ueno H, Matsuda T, Hashimoto S, Amaya F, Kitamura Y, Tanaka M, et al. Contributions of high mobility group box protein in experimental and clinical acute lung injury. Am J Respir Crit Care Med. 2004;170:1310–6. doi:10.​1164/​rccm.​200402-188OC.PubMedCrossRef
19.
go back to reference Hatada T, Wada H, Nobori T, Okabayashi K, Maruyama K, Abe Y, et al. Plasma concentrations and importance of high mobility group box protein in the prognosis of organ failure in patients with disseminated intravascular coagulation. Thromb Haemost. 2005;94:975–9.PubMed Hatada T, Wada H, Nobori T, Okabayashi K, Maruyama K, Abe Y, et al. Plasma concentrations and importance of high mobility group box protein in the prognosis of organ failure in patients with disseminated intravascular coagulation. Thromb Haemost. 2005;94:975–9.PubMed
20.
21.
go back to reference Pullerits R, Bokarewa M, Dahlberg L, Tarkowski A. Synovial fluid expression of autoantibodies specific for rage relates to less erosive course of rheumatoid arthritis. Rheumatology (Oxford). 2007;46:1367–71. doi:10.1093/rheumatology/kem141.CrossRef Pullerits R, Bokarewa M, Dahlberg L, Tarkowski A. Synovial fluid expression of autoantibodies specific for rage relates to less erosive course of rheumatoid arthritis. Rheumatology (Oxford). 2007;46:1367–71. doi:10.​1093/​rheumatology/​kem141.CrossRef
22.
go back to reference Pullerits R, Bokarewa M, Dahlberg L, Tarkowski A. Decreased levels of soluble receptor for advanced glycation end products in patients with rheumatoid arthritis indicating deficient inflammatory control. Arthritis Res Ther. 2005;7:R817–24. doi:10.1186/ar1749.PubMedCrossRef Pullerits R, Bokarewa M, Dahlberg L, Tarkowski A. Decreased levels of soluble receptor for advanced glycation end products in patients with rheumatoid arthritis indicating deficient inflammatory control. Arthritis Res Ther. 2005;7:R817–24. doi:10.​1186/​ar1749.PubMedCrossRef
23.
go back to reference Bopp C, Hofer S, Weitz J, Bierhaus A, Nawroth PP, Martin E, et al. sRAGE is elevated in septic patients and associated with patients outcome. J Surg Res 2008;147:79–83.PubMedCrossRef Bopp C, Hofer S, Weitz J, Bierhaus A, Nawroth PP, Martin E, et al. sRAGE is elevated in septic patients and associated with patients outcome. J Surg Res 2008;147:79–83.PubMedCrossRef
25.
go back to reference Green MC, Sweet HO, Bunker LE. Tight-skin, a new mutation of the mouse causing excessive growth of connective tissue and skeleton. Am J Pathol. 1976;82:493–512.PubMed Green MC, Sweet HO, Bunker LE. Tight-skin, a new mutation of the mouse causing excessive growth of connective tissue and skeleton. Am J Pathol. 1976;82:493–512.PubMed
27.
go back to reference LeRoy EC, Black C, Fleischmajer R, Jablonska S, Krieg T, Medsger TA Jr, et al. Scleroderma (systemic sclerosis): Classification, subsets and pathogenesis. J Rheumatol. 1988;15:202–5.PubMed LeRoy EC, Black C, Fleischmajer R, Jablonska S, Krieg T, Medsger TA Jr, et al. Scleroderma (systemic sclerosis): Classification, subsets and pathogenesis. J Rheumatol. 1988;15:202–5.PubMed
28.
go back to reference Clements PJ, Lachenbruch PA, Seibold JR, Zee B, Steen VD, Brennan P, et al. Skin thickness score in systemic sclerosis: an assessment of interobeservar variability in 3 independent studies. J Rheumatol. 1993;20:1892–6.PubMed Clements PJ, Lachenbruch PA, Seibold JR, Zee B, Steen VD, Brennan P, et al. Skin thickness score in systemic sclerosis: an assessment of interobeservar variability in 3 independent studies. J Rheumatol. 1993;20:1892–6.PubMed
31.
go back to reference Kokkola R, Li J, Sundberg E, Aveberger AC, Palmblad K, Yang H, et al. Successful treatment of collagen-induced arthritis in mice and rats by targeting extracellular high mobility group box chromosomal protein 1 activity. Arthritis Rheum. 2003;48:2052–8. doi:10.1002/art.11161.PubMedCrossRef Kokkola R, Li J, Sundberg E, Aveberger AC, Palmblad K, Yang H, et al. Successful treatment of collagen-induced arthritis in mice and rats by targeting extracellular high mobility group box chromosomal protein 1 activity. Arthritis Rheum. 2003;48:2052–8. doi:10.​1002/​art.​11161.PubMedCrossRef
32.
go back to reference Kuniyasu H, Chihara Y, Takahashi T. Co-expression of receptor for advanced glycation end products and the ligand amphoterin associates closely with metastasis of colorectal cancer. Oncol Rep. 2003;10:445–8.PubMed Kuniyasu H, Chihara Y, Takahashi T. Co-expression of receptor for advanced glycation end products and the ligand amphoterin associates closely with metastasis of colorectal cancer. Oncol Rep. 2003;10:445–8.PubMed
34.
go back to reference Alecu M, Geleriu L, Coman G, Galatescu L. The interleukin-1, interleukin-2, interleukin-6 and tumour necrosis factor alpha serological levels in localised and systemic sclerosis. Rom J Intern Med. 1998;36:251–9.PubMed Alecu M, Geleriu L, Coman G, Galatescu L. The interleukin-1, interleukin-2, interleukin-6 and tumour necrosis factor alpha serological levels in localised and systemic sclerosis. Rom J Intern Med. 1998;36:251–9.PubMed
38.
go back to reference Yamagishi S, Adachi H, Nakamura K, Matsui T, Jinnouchi Y, Takenaka K, et al. Positive association between serum levels of advanced glycation end products and the soluble form of receptor for advanced glycation end products in nondiabetic subjects. Metabolism. 2006;55:1227–31. doi:10.1016/j.metabol.2006.05.007.PubMedCrossRef Yamagishi S, Adachi H, Nakamura K, Matsui T, Jinnouchi Y, Takenaka K, et al. Positive association between serum levels of advanced glycation end products and the soluble form of receptor for advanced glycation end products in nondiabetic subjects. Metabolism. 2006;55:1227–31. doi:10.​1016/​j.​metabol.​2006.​05.​007.PubMedCrossRef
39.
go back to reference Park JS, Svetkauskaite D, He Q, Kim JY, Strassheim D, Ishizaka A, et al. Involvement of toll-like receptors 2 and 4 in cellular activation by high mobility group box 1 protein. J Biol Chem. 2003;279:7370–7. doi:10.1074/jbc.M306793200.PubMedCrossRef Park JS, Svetkauskaite D, He Q, Kim JY, Strassheim D, Ishizaka A, et al. Involvement of toll-like receptors 2 and 4 in cellular activation by high mobility group box 1 protein. J Biol Chem. 2003;279:7370–7. doi:10.​1074/​jbc.​M306793200.PubMedCrossRef
40.
go back to reference Lin KI, Kao YY, Kuo HK, Yang WB, Chou A, Lin HH, et al. Reishi polysaccharides induce immunoglobulin production through the tlr4/tlr2-mediated induction of transcription factor blimp-1. J Biol Chem. 2006;281:24111–23. doi:10.1074/jbc.M601106200.PubMedCrossRef Lin KI, Kao YY, Kuo HK, Yang WB, Chou A, Lin HH, et al. Reishi polysaccharides induce immunoglobulin production through the tlr4/tlr2-mediated induction of transcription factor blimp-1. J Biol Chem. 2006;281:24111–23. doi:10.​1074/​jbc.​M601106200.PubMedCrossRef
41.
go back to reference Ek M, Popovic K, Harris HE, Naucler CS, Wahren-Herlenius M. Increased extracellular levels of the novel proinflammatory cytokine high mobility group box chromosomal protein 1 in minor salivary glands of patients with Sjögren’s syndrome. Arthritis Rheum. 2006;54:2289–94. doi:10.1002/art.21969.PubMedCrossRef Ek M, Popovic K, Harris HE, Naucler CS, Wahren-Herlenius M. Increased extracellular levels of the novel proinflammatory cytokine high mobility group box chromosomal protein 1 in minor salivary glands of patients with Sjögren’s syndrome. Arthritis Rheum. 2006;54:2289–94. doi:10.​1002/​art.​21969.PubMedCrossRef
42.
go back to reference Popovic K, Ek M, Espinosa A, Padyukov L, Harris HE, Wahren-Herlenius M, et al. Increased expression of the novel proinflammatory cytokine high mobility group box chromosomal protein 1 in skin lesions of patients with lupus erythematosus. Arthritis Rheum. 2005;52:3639–45. doi:10.1002/art.21398.PubMedCrossRef Popovic K, Ek M, Espinosa A, Padyukov L, Harris HE, Wahren-Herlenius M, et al. Increased expression of the novel proinflammatory cytokine high mobility group box chromosomal protein 1 in skin lesions of patients with lupus erythematosus. Arthritis Rheum. 2005;52:3639–45. doi:10.​1002/​art.​21398.PubMedCrossRef
43.
go back to reference Bruchfeld A, Qureshi AR, Lindholm B, Barany P, Yang L, Stenvinkel P, et al. High mobility group box protein-1 correlates with renal function in chronic kidney disease (CKD). Mol Med. 2008;14:1–15. doi:10.2119/2007-00107.CrossRef Bruchfeld A, Qureshi AR, Lindholm B, Barany P, Yang L, Stenvinkel P, et al. High mobility group box protein-1 correlates with renal function in chronic kidney disease (CKD). Mol Med. 2008;14:1–15. doi:10.​2119/​2007-00107.CrossRef
44.
go back to reference van Zoelen MA, Yang H, Florquin S, Meijers JC, Akira S, Arnold B, et al. Role of toll-like receptors 2 and 4, and the receptor for advanced glycation end products (rage) in HMGB1 induced inflammation in vivo. Shock. 2008. PMID: 18665043. van Zoelen MA, Yang H, Florquin S, Meijers JC, Akira S, Arnold B, et al. Role of toll-like receptors 2 and 4, and the receptor for advanced glycation end products (rage) in HMGB1 induced inflammation in vivo. Shock. 2008. PMID: 18665043.
46.
go back to reference Sundberg E, Grundtman C, Af Klint E, Lindberg J, Ernestam S, Ulfgren AK, et al. Systemic tnf blockade does not modulate synovial expression of the pro-inflammatory mediator hmgb1 in rheumatoid arthritis patients—a prospective clinical study. Arthritis Res Ther. 2008;10:R33. doi:10.1186/ar2387.PubMedCrossRef Sundberg E, Grundtman C, Af Klint E, Lindberg J, Ernestam S, Ulfgren AK, et al. Systemic tnf blockade does not modulate synovial expression of the pro-inflammatory mediator hmgb1 in rheumatoid arthritis patients—a prospective clinical study. Arthritis Res Ther. 2008;10:R33. doi:10.​1186/​ar2387.PubMedCrossRef
47.
go back to reference Kielty CM, Raghunath M, Siracusa LD, Sherratt MJ, Peters R, Shuttleworth CA, et al. The tight skin mouse: demonstration of mutant fibrillin-1 production and assembly into abnormal microfibrils. J Cell Biol. 1998;140:1159–66. doi:10.1083/jcb.140.5.1159.PubMedCrossRef Kielty CM, Raghunath M, Siracusa LD, Sherratt MJ, Peters R, Shuttleworth CA, et al. The tight skin mouse: demonstration of mutant fibrillin-1 production and assembly into abnormal microfibrils. J Cell Biol. 1998;140:1159–66. doi:10.​1083/​jcb.​140.​5.​1159.PubMedCrossRef
50.
go back to reference Taguchi A, Blood DC, del Toro G, Canet A, Lee DC, Qu W, et al. Blockade of rage-amphoterin signalling suppresses tumour growth and metastases. Nature. 2000;405:354–60. doi:10.1038/35012626.PubMedCrossRef Taguchi A, Blood DC, del Toro G, Canet A, Lee DC, Qu W, et al. Blockade of rage-amphoterin signalling suppresses tumour growth and metastases. Nature. 2000;405:354–60. doi:10.​1038/​35012626.PubMedCrossRef
51.
go back to reference Chavakis T, Bierhaus A, Al-Fakhri N, Schneider D, Witte S, Linn T, et al. The pattern recognition receptor (rage) is a counterreceptor for leukocyte integrins: a novel pathway for inflammatory cell recruitment. J Exp Med. 2003;198:1507–15. doi:10.1084/jem.20030800.PubMedCrossRef Chavakis T, Bierhaus A, Al-Fakhri N, Schneider D, Witte S, Linn T, et al. The pattern recognition receptor (rage) is a counterreceptor for leukocyte integrins: a novel pathway for inflammatory cell recruitment. J Exp Med. 2003;198:1507–15. doi:10.​1084/​jem.​20030800.PubMedCrossRef
52.
go back to reference Nakamura K, Yamagishi S, Adachi H, Kurita-Nakamura Y, Matsui T, Yoshida T, et al. Serum levels of srage, the soluble form of receptor for advanced glycation end products, are associated with inflammatory markers in patients with type 2 diabetes. Mol Med. 2007;13:1–9. doi:10.2119/2006-00090.CrossRef Nakamura K, Yamagishi S, Adachi H, Kurita-Nakamura Y, Matsui T, Yoshida T, et al. Serum levels of srage, the soluble form of receptor for advanced glycation end products, are associated with inflammatory markers in patients with type 2 diabetes. Mol Med. 2007;13:1–9. doi:10.​2119/​2006-00090.CrossRef
53.
Metadata
Title
Clinical Significance of Serum HMGB-1 and sRAGE Levels in Systemic Sclerosis: Association with Disease Severity
Authors
Ayumi Yoshizaki
Kazuhiro Komura
Yohei Iwata
Fumihide Ogawa
Toshihide Hara
Eiji Muroi
Motoi Takenaka
Kazuhiro Shimizu
Minoru Hasegawa
Manabu Fujimoto
Shinichi Sato
Publication date
01-03-2009
Publisher
Springer US
Published in
Journal of Clinical Immunology / Issue 2/2009
Print ISSN: 0271-9142
Electronic ISSN: 1573-2592
DOI
https://doi.org/10.1007/s10875-008-9252-x

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