Abstract
Recent studies indicate that high-mobility group box protein 1 (HMGB1) contributes to the pathogenesis of diverse autoimmune disorders. It induces the production of interferon-alpha (IFN-alpha) and tumor necrosis factor alpha (TNF-alpha) in vitro. In the present study, plasma HMGB1, TNF-alpha, and IFN-alpha were determined with ELISA in 37 patients with systemic lupus erythematosus (SLE) and 39 age- and sex-matched healthy controls (HC). The possible associations of these cytokines with disease activities, autoantibodies, and certain laboratory parameters were also explored. The plasma levels of HMGB1, TNF-alpha, and IFN-alpha were increased in SLE patients compared with those of HC (P < 0.05). Moreover, the levels of HMGB1 and TNF-alpha in the active SLE patients were elevated compared with those in inactive patients and HC. Additionally, plasma HMGB1 was positively correlated with peripheral neutrophils, and plasma TNF-alpha was positively correlated with anti-Sm, ESR and CRP, while plasma IFN-alpha was inversely correlated with the age and platelet level in SLE patients. Our data indicated that increased plasma HMGB1 was associated with disease activity in SLE, which was similar to TNF-alpha. High level of plasma IFN-alpha may be related to nephritis and thrombocytopenia in SLE.
Similar content being viewed by others
References
Mock CC, Lau CS (2003) Pathogenesis of systemic lupus erythematosus. J Clin Pathol 56:481–490
Niewold TB, Hua J, Lehman TJ et al (2007) High serum IFN-alpha activity is a heritable risk factor for systemic lupus erythematosus. Genes Immun 8:492–502
Gota C, Calabrese L (2003) Induction of clinical autoimmune disease by therapeutic interferon-alpha. Autoimmunity 36:511–518
Feldmann M, Maini RN (2001) Anti-TNF alpha therapy of rheumatoid arthritis: what have we learned? Annu Rev Immunol 19:163–196
Studnicka-Benke A, Steiner G, Petera P et al (1996) Tumour necrosis factor alpha and its soluble receptors parallel clinical disease and autoimmune activity in systemic lupus erythematosus. Br J Rheumatol 35:1067–1074
Aringer M, Smolen JS (2008) The role of tumor necrosis factor-alpha in systemic lupus erythematosus. Arthritis Res Ther 10:202
Li J, Xie H, Wen T et al (2010) Expression of high mobility group box chromosomal protein 1 and its modulating effects on downstream cytokines in systemic lupus erythematosus. J Rheumatol 37:766–775
Thomas JO, Travers AA (2001) HMG1 and 2, and related ‘architectural’ DNA-binding proteins. Trends Biochem Sci 26:167–174
Bianchi ME, Agresti A (2005) HMG proteins: dynamic players in gene regulation and differentiation. Curr Opin Genet Dev 15:496–506
Scaffidi P, Misteli T, Bianchi ME (2002) Release of chromatin protein HMGB1 by necrotic cells triggers inflammation. Nature 418:191–195
Wang H, Bloom O, Zhang M et al (1999) HMG-1 as a late mediator of endotoxin lethality in mice. Science 285:248–251
Lotze MT, Tracey KJ (2005) High-mobility group box 1 protein (HMGB1): nuclear weapon in the immune arsenal. Nat Rev Immunol 5:331–342
Abraham E, Arcaroli J, Carmody A et al (2000) HMG-1 as a mediator of acute lung inflammation. J Immunol 165:2950–2954
Park JS, Gamboni-Robertson F, He Q et al (2006) High mobility group box 1 protein interacts with multiple Toll-like receptors. Am J Physiol Cell Physiol 290:C917–C924
Andersson U, Wang H, Palmblad K et al (2000) High mobility group 1 protein (HMG-1) stimulates proinflammatory cytokine synthesis in human monocytes. J Exp Med 192:565–570
Park JS, Svetkauskaite D, He Q et al (2004) Involvement of toll-like receptors 2 and 4 in cellular activation by high mobility group box 1 protein. J Biol Chem 279:7370–7377
Kokkola R, Sundberg E, Ulfgren AK et al (2002) High mobility group box chromosomal protein 1: a novel proinflammatory mediator in synovitis. Arthritis Rheum 46:2598–2603
Taniguchi N, Kawahara K, Yone K et al (2003) High mobility group box chromosomal protein 1 plays a role in the pathogenesis of rheumatoid arthritis as a novel cytokine. Arthritis Rheum 48:971–981
Pullerits R, Jonsson IM, Verdrengh M et al (2003) High mobility group box chromosomal protein 1, a DNA binding cytokine, induces arthritis. Arthritis Rheum 48:1693–1700
Kokkola R, Li J, Sundberg E et al (2003) Successful treatment of collagen-induced arthritis in mice and rats by targeting extracellular high mobility group box chromosomal protein 1 activity. Arthritis Rheum 48:2052–2058
Yoshizaki A, Komura K, Iwata Y et al (2009) Clinical significance of serum HMGB-1 and sRAGE levels in systemic sclerosis: association with disease severity. J Clin Immunol 29:180–189
Popovic K, Ek M, Espinosa A et al (2005) Increased expression of the novel proinflammatory cytokine high mobility group box chromosomal protein 1 in skin lesions of patients with lupus erythematosus. Arthritis Rheum 52:3639–3645
Ek M, Popovic K, Harris HE et al (2006) Increased extracellular levels of the novel proinflammatory cytokine high mobility group box chromosomal protein 1 in minor salivary glands of patients with Sjogren’s syndrome. Arthritis Rheum 54:2289–2294
Tian J, Avalos AM, Mao SY et al (2007) Toll-like receptor 9-dependent activation by DNA-containing immune complexes is mediated by HMGB1 and RAGE. Nat Immunol 8:487–496
Dumitriu IE, Baruah P, Bianchi ME et al (2005) Requirement of HMGB1 and RAGE for the maturation of human plasmacytoid dendritic cells. Eur J Immunol 35:2184–2190
Qing X, Pitashny M, Thomas DB et al (2008) Pathogenic anti-DNA antibodies modulate gene expression in mesangial cells: involvement of HMGB1 in anti-DNA antibody-induced renal injury. Immunol Lett 121:61–73
Hochberg MC (1997) Updating the American college of rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 40:1725
Sigal LH (2007) Basic science for the clinician 42: handling the corpses: apoptosis, necrosis, nucleosomes and (quite possibly) the immunopathogenesis of SLE. J Clin Rheumatol 13:44–48
Midgley A, McLaren Z, Moots RJ et al (2009) The role of neutrophil apoptosis in juvenile-onset systemic lupus erythematosus. Arthritis Rheum 60:2390–2401
Liu G, Wang J, Park YJ et al (2008) High mobility group protein-1 inhibits phagocytosis of apoptotic neutrophils through binding to phosphatidylserine. J Immunol 181:4240–4246
Urbonaviciute V, Furnrohr BG, Meister S et al (2008) Induction of inflammatory and immune responses by HMGB1-nucleosome complexes: implications for the pathogenesis of SLE. J Exp Med 205:3007–3018
Rovere-Querini P, Capobianco A, Scaffidi P et al (2004) HMGB1 is an endogenous immune adjuvant released by necrotic cells. EMBO Rep 5:825–830
Bennett L, Palucka AK, Arce E et al (2003) Interferon and granulopoiesis signatures in systemic lupus erythematosus blood. J Exp Med 197:711–723
Kirou KA, Lee C, George S et al (2005) Activation of the interferon-alpha pathway identifies a subgroup of systemic lupus erythematosus patients with distinct serologic features and active disease. Arthritis Rheum 52:1491–1503
Iannacone M, Sitia G, Isogawa M et al (2008) Platelets prevent IFN-alpha/beta-induced lethal hemorrhage promoting CTL-dependent clearance of lymphocytic choriomeningitis virus. Proc Natl Acad Sci USA 105:629–634
Yamane A, Nakamura T, Suzuki H et al (2008) Interferon-alpha 2b-induced thrombocytopenia is caused by inhibition of platelet production but not proliferation and endomitosis in human megakaryocytes. Blood 112:542–550
Palucka AK, Blanck JP, Bennett L et al (2005) Cross-regulation of TNF and IFN-alpha in autoimmune diseases. Proc Natl Acad Sci USA 102:3372–3377
Lee HM, Mima T, Sugino H et al (2009) Interactions among type I and type II interferon, tumor necrosis factor, and beta-estradiol in the regulation of immune response-related gene expressions in systemic lupus erythematosus. Arthritis Res Ther 11:R1
Grondal G, Gunnarsson I, Ronnelid J et al (2000) Cytokine production, serum levels and disease activity in systemic lupus erythematosus. Clin Exp Rheumatol 18:565–570
Acknowledgments
This study was supported by grants from the National Natural Science Foundation of China (No. 30371304) and the Foundation of Shandong Province Science & Technical Committee (No. 2009GG10002008). The authors would like to thank Dr. Jian-feng Li for his help in the manuscript revision.
Conflict of interest
The authors declare that they have no conflict of interest.
Author information
Authors and Affiliations
Corresponding author
Additional information
C. Ma and Y. Jiao contributed equally.
Rights and permissions
About this article
Cite this article
Ma, Cy., Jiao, Yl., Zhang, J. et al. Elevated plasma level of HMGB1 is associated with disease activity and combined alterations with IFN-alpha and TNF-alpha in systemic lupus erythematosus. Rheumatol Int 32, 395–402 (2012). https://doi.org/10.1007/s00296-010-1636-6
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00296-010-1636-6