HMGB1 Concentration In Vivo
Various techniques have been used to quantify extra-cellular HMGB1 in peripheral blood or other biological specimens. The western blotting was initially used [11, 80] before an easier and more sensitive commercial ELISA test became available [81,82].
This new assay allowed more extensive studies on the levels of HMGB1 during various conditions, even if some concerns have been raised regarding the possible interference of factors that may mask HMGB1 in the serum, such as antibodies [82]. This may notably explain some observed discrepancies between the severity of sepsis and the concentration of HMGB1 in serum [83].To investigate this question, our team has recently developed an original and very sensitive gel shift assay to quantify HMGB1 [84]. This assay is based on the ability of HMGB1 to bind with extremely high affinity to a particular form of double-stranded DNA, the hemicatenated DNA loops [5,85]. The protocol was then modified to introduce an additional step where HMGB1 is chemically dissociated from other molecules, such as antibodies. Some unpublished work from our lab suggested that the ELISA would often underestimate the effective amount of HMGB1 in serum (S.Barnay, manuscript submitted for publication). Whatever the method used, HMGB1 concentrations are usually undetectable or very low (below 1 ng/ml) in serum or plasma collected from healthy controls, even if frequent occurrence of detectable HMGB1 can be scarcely observed in individuals without any apparent condition [84,86]. On the contrary, increased concentrations of HMGB1 have been detected in the serum of patients with severe sepsis [10,83]. The range of HMGB1 levels in this setting appears to be large (from 1 to 160 ng/ml) and may depend on the method used. However, HMGB1 concentrations globally correlate in this setting with clinical outcome, the highest levels being observed most often in non-survivors.
Importantly, much higher concentrations (up to 10 μg∕ml) can be measured in vivo, when samples are collected from local inflammatory sites. This has been notably observed in bronchoalveolar lavages from patients suffering from acute lung injury [87], synovial fluid of individuals with rheumatoid arthritis [52] and in cervico-vaginal swabs from women with genital herpes (C. Borde, unpublished data).In the context of HIV-1 infection, HMGB1 levels have been measured in plasma samples from healthy volunteers and from untreated HIV infected patients at various stages of their disease [88]. Three patient categories have been defined: group A (n = 14), with preserved immunological status (CD4 cell count above 600∕μl) and a low viral load (below 2000 c∕ml); group B (n = 13), with deteriorated immunological status (CD4 cell count below 400∕μl) and a high viral load (above 20000 c∕ml); group C (n = 16), with a deteriorated immunological status, a high viral load and an opportunistic disease at the moment of sampling. Despite the limited size of the different groups, the authors found that HIV infected patients globally displayed increased concentrations of HMGB1 in plasma (median 5.3 ng∕ml, range 0.5-87.5) compared with uninfected controls (median 1.4 ng∕ml, range 0.0-4.4; p(median 4.7 ng∕ml, range 1.7-87.5; pJH, et al. Inflammation-promoting activity of HMGB1 on human microvascular endothelial cells. Blood 2003 Apr 1;101(7):2652-60.[29] 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 Nov 17;198(10):1507-15.
[30] Orlova VV, Choi EY, Xie C, Chavakis E, Bierhaus A, Ihanus E, et al. A novel pathway of HMGB1-mediated inflammatory cell recruitment that requires Mac-1-integrin. EMBO J 2007 Feb 21;26(4):1129-39.
[31] Messmer D, Yang H, Telusma G, Knoll F, Li J, Messmer B, et al.
High mobility group box protein 1: an endogenous signal for dendritic cell maturation and Th1 polarization. J Immunol 2004 Jul 1;173(1):307-13.[32] Rovere-Querini P, Capobianco A, Scaffidi P, Valentinis B, Catalanotti F, Giazzon M, et al. HMGB1 is an endogenous immune adjuvant released by necrotic cells. EMBO Rep 2004 Aug;5(8):825-30.
[33] Semino C, Angelini G, Poggi A, Rubartelli A. NK/iDC interaction results in IL-18 secretion by DCs at the synaptic cleft followed by NK cell activation and release of the DC maturation factor HMGB1. Blood 2005 Jul 15;106(2):609-16.
[34] DeMarco RA, Fink MP, Lotze MT. Monocytes promote natural killer cell interferon gamma production in response to the endogenous danger signal HMGB1. Mol Immunol 2005 Feb;42(4):433-44.
[35] Palumbo R, Sampaolesi M, De Marchis F, Tonlorenzi R, Colombetti S, Mondino A, et al. Extracellular HMGB1, a signal of tissue damage, induces mesoangioblast migration and proliferation. J Cell Biol 2004 Feb 2;164(3):441-9.
[36] Limana F, Germani A, Zacheo A, Kajstura J, Di Carlo A, Borsellino G, et al. Exogenous high-mobility group box 1 protein induces myocardial regeneration after infarction via enhanced cardiac C-kit+ cell proliferation and differentiation. Circ Res 2005 Oct 14;97(8):e73-83.
[37] Mitola S, Belleri M, Urbinati C, Coltrini D, Sparatore B, Pedrazzi M, et al. Cutting edge: extracellular high mobility group box-1 protein is a proangiogenic cytokine. J Immunol 2006 Jan 1;176(1):12-5.
[38] Straino S, Di Carlo A, Mangoni A, De Mori R, Guerra L, Maurelli R, et al. High-mobility group box 1 protein in human and murine skin: involvement in wound healing. J Invest Dermatol 2008 Jun;128(6):1545-53.
[39] Huttunen HJ, Fages C, Kuja-Panula J, Ridley AJ, Rauvala H. Receptor for advanced glycation end products- binding COOH-terminal motif of amphoterin inhibits invasive migration and metastasis. Cancer Res 2002 Aug 15;62(16):4805-11.
[40] Kuniyasu H, Oue N, Wakikawa A, Shigeishi H, Matsutani N, Kuraoka K, et al.
Expression of receptors for advanced glycation end-products (RAGE) is closely associated with the invasive and metastatic activity of gastric cancer. J Pathol 2002 Feb;196(2):163-70.[41] 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 Mar-Apr;10(2):445-8.
[42] Kuniyasu H, Yano S, Sasaki T, Sasahira T, Sone S, Ohmori H. Colon cancer cell-derived high mobility group 1/amphoterin induces growth inhibition and apoptosis in macrophages. Am J Pathol 2005 Mar;166(3):751-60.
[43] Wang H, Yang H, Tracey KJ. Extracellular role of HMGB1 in inflammation and sepsis. J Intern Med 2004 Mar;255(3):320-31.
[44] Yang H, Ochani M, Li J, Qiang X, Tanovic M, Harris HE, et al. Reversing established sepsis with antagonists of endogenous high-mobility group box 1. Proc Natl Acad Sci USA 2004 Jan 6;101(1):296-301.
[45] Jaulmes A, Thierry S, Janvier B, Raymondjean M, Marechal V. Activation of sPLA2-IIA and PGE2 production by high mobility group protein B1 in vascular smooth muscle cells sensitized by IL-1beta. FASEB J 2006 Aug;20(10):1727-9.
[46] Rouhiainen A, Tumova S, Valmu L, Kalkkinen N, Rauvala H. Pivotal advance: analysis of proinflammatory activity of highly purified eukaryotic recombinant HMGB1 (amphoterin). J Leukoc Biol 2007 Jan;81(1):49-58.
[47] 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 May;8(5):487-96.
[48] Ivanov S, Dragoi AM, Wang X, Dallacosta C, Louten J, Musco G, et al. A novel role for HMGB1 in TLR9- mediated inflammatory responses to CpG-DNA. Blood 2007 Sep 15;110(6):1970-81.
[49] Youn JH, Oh YJ, Kim ES, Choi JE, Shin JS. High mobility group box 1 protein binding to lipopolysaccharide facilitates transfer of lipopolysaccharide to CD14 and enhances lipopolysaccharide-mediated TNF-alpha production in human monocytes.
J Immunol 2008 Apr 1;180(7):5067-74.[50] 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 Jul;48(7):2052-8.
[51] Pullerits R, Jonsson IM, Verdrengh M, Bokarewa M, Andersson U, Erlandsson-Harris H, et al. High mobility group box chromosomal protein 1, a DNA binding cytokine, induces arthritis. Arthritis Rheum 2003 Jun;48(6):1693-700.
[52] Taniguchi N, Kawahara K, Yone K, Hashiguchi T, Yamakuchi M, Goto M, et al. High mobility group box chromosomal protein 1 plays a role in the pathogenesis of rheumatoid arthritis as a novel cytokine. Arthritis Rheum 2003 Apr;48(4):971-81.
[53] Volp K, Brezniceanu ML, Bosser S, Brabletz T, Kirchner T, Gottel D, et al. Increased expression of high mobility group box 1 (HMGB1) is associated with an elevated level of the antiapoptotic c-IAP2 protein in human colon carcinomas. Gut 2006 Feb;55(2):234-42.
[54] Kuniyasu H, Chihara Y, Kondo H, Ohmori H, Ukai R. Amphoterin induction in prostatic stromal cells by androgen deprivation is associated with metastatic prostate cancer. Oncol Rep 2003 Nov-Dec;10(6):1863-8.
[55] 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 May 18;405(6784):354-60.
[56] Apetoh L, Ghiringhelli F, Tesniere A, Obeid M, Ortiz C, Criollo A, et al. Toll-like receptor 4-dependent contribution of the immune system to anticancer chemotherapy and radiotherapy. Nat Med 2007 Sep;13(9):1050-9.
[57] Curtin JF, Liu N, Candolfi M, Xiong W, Assi H, Yagiz K, et al. HMGB1 mediates endogenous TLR2 activation and brain tumor regression. PLoS Med 2009 Jan 13;6(1):e10.
[58] Inoue K, Kawahara K, Biswas KK, Ando K, Mitsudo K, Nobuyoshi M, et al. HMGB1 expression by activated vascular smooth muscle cells in advanced human atherosclerosis plaques.
Cardiovasc Pathol 2007 May- Jun;16(3):136-43.[59] Porto A, Palumbo R, Pieroni M, Aprigliano G, Chiesa R, Sanvito F, et al. Smooth muscle cells in human atherosclerotic plaques secrete and proliferate in response to high mobility group box 1 protein. FASEB J 2006 Dec;20(14):2565-6.
[60] Decrion AZ, Dichamp I, Varin A, Herbein G. HIV and inflammation. Curr HIV Res2005 Jul;3(3):243-59.
[61] Xu D, Komai-Koma M, Liew FY. Expression and function of Toll-like receptor on T cells. Cell Immunol 2005 Feb;233(2):85-9.
[62] Hemmi H, Akira S. TLR signalling and the function of dendritic cells. Chem Immunol Allergy 2005;86:120-35.
[63] Kaisho T, Akira S. Toll-like receptors as adjuvant receptors. Biochim Biophys Acta 2002 Feb 13;1589(1):1-13.
[64] Akira S, Yamamoto M, Takeda K. Role of adapters in Toll-like receptor signalling. Biochem Soc Trans 2003 Jun;31(Pt 3):637-42.
[65] de Witte L, Nabatov A, Pion M, Fluitsma D, de Jong MA, de Gruijl T, et al. Langerin is a natural barrier to HIV-1 transmission by Langerhans cells. Nat Med 2007 Mar;13(3):367-71.
[66] Mailliard RB, Son YI, Redlinger R, Coates PT, Giermasz A, Morel PA, et al. Dendritic cells mediate NK cell help for Th1 and CTL responses: two-signal requirement for the induction of NK cell helper function. J Immunol 2003 Sep 1;171(5):2366-73.
[67] Dumitriu IE, Baruah P, Bianchi ME, Manfredi AA, Rovere-Querini P. Requirement of HMGB1 and RAGE for the maturation of human plasmacytoid dendritic cells. Eur J Immunol 2005 Jul;35(7):2184-90.
[68] Saidi H, Melki MT, Gougeon ML. HMGB1-dependent triggering of HIV-1 replication and persistence in dendritic cells as a consequence of NK-DC cross-talk. PLoS ONE 2008;3(10):e3601.
[69] Naghavi MH, Nowak P, Andersson J, Sonnerborg A, Yang H, Tracey KJ, et al. Intracellular high mobility group B1 protein (HMGB1) represses HIV-1 LTR-directed transcription in a promoter- and cell-specific manner. Virology 2003 Sep 15;314(1):179-89.
[70] Alfano M, Poli G. Role of cytokines and chemokines in the regulation of innate immunity and HIV infection. Mol Immunol 2005 Feb;42(2):161-82.
[71] Thierry S, Gozlan J, Jaulmes A, Boniface R, Nasreddine N, Strauss F, et al. High-mobility group box 1 protein induces HIV-1 expression from persistently infected cells. AIDS 2007 Jan 30;21(3):283-92.
[72] Nowak P, Barqasho B, Treutiger CJ, Harris HE, Tracey KJ, Andersson J, et al. HMGB1 activates replication of latent HIV-1 in a monocytic cell-line, but inhibits HIV-1 replication in primary macrophages. Cytokine 2006 Apr;34(1-2):17-23.
[73] Chu JJ, Ng ML. The mechanism of cell death during West Nile virus infection is dependent on initial infectious dose. J Gen Virol 2003 Dec;84(Pt 12):3305-14.
[74] Wang H, Ward MF, Fan XG, Sama AE, Li W. Potential role of high mobility group box 1 in viral infectious diseases. Viral Immunol 2006 Spring;19(1):3-9.
[75] Plymale DR, Tang DS, Comardelle AM, Fermin CD, Lewis DE, Garry RF. Both necrosis and apoptosis contribute to HIV-1-induced killing of CD4 cells. AIDS 1999 Oct 1;13(14):1827-39.
[76] Lenardo MJ, Angleman SB, Bounkeua V, Dimas J, Duvall MG, Graubard MB, et al. Cytopathic killing of peripheral blood CD4(+) T lymphocytes by human immunodeficiency virus type 1 appears necrotic rather than apoptotic and does not require env. J Virol 2002 May;76(10):5082-93.
[77] Cassetta L, Fortunato O, Adduce L, Rizzi C, Hering J, Rovere-Querini P, et al. Extracellular high mobility group box-1 inhibits R5 and X4 HIV-1 strains replication in mononuclear phagocytes without induction of chemokines and cytokines. AIDS 2009 Feb 3.
[78] Lane BR, Markovitz DM, Woodford NL, Rochford R, Strieter RM, Coffey MJ. TNF-alpha inhibits HIV-1 replication in peripheral blood monocytes and alveolar macrophages by inducing the production of RANTES and decreasing C-C chemokine receptor 5 (CCR5) expression. J Immunol 1999 Oct 1;163(7):3653-61.
[79] Biswas P, Poli G, Kinter AL, Justement JS, Stanley SK, Maury WJ, et al. Interferon gamma induces the expression of human immunodeficiency virus in persistently infected promonocytic cells (U1) and redirects the production of virions to intracytoplasmic vacuoles in phorbol myristate acetate-differentiated U1 cells. J Exp Med 1992 Sep 1;176(3):739-50.
[80] Sunden-Cullberg J, Norrby-Teglund A, Rouhiainen A, Rauvala H, Herman G, Tracey KJ, et al. Persistent elevation of high mobility group box-1 protein (HMGB1) in patients with severe sepsis and septic shock. Crit Care Med 2005 Mar;33(3):564-73.
[81] Yamada S, Inoue K, Yakabe K, Imaizumi H, Maruyama I. High mobility group protein 1 (HMGB1) quantified by ELISA with a monoclonal antibody that does not cross-react with HMGB2. Clin Chem 2003 Sep;49(9):1535-7.
[82] Urbonaviciute V, Furnrohr BG, Weber C, Haslbeck M, Wilhelm S, Herrmann M, et al. Factors masking HMGB1 in human serum and plasma. J Leukoc Biol 2007 Jan;81(1):67-74.
[83] Gibot S, Massin F, Cravoisy A, Barraud D, Nace L, Levy B, et al. High-mobility group box 1 protein plasma concentrations during septic shock. Intensive Care Med 2007 Aug;33(8):1347-53.
[84] Gaillard C, Borde C, Gozlan J, Marechal V, Strauss F. A high-sensitivity method for detection and measurement of HMGB1 protein concentration by high-affinity binding to DNA hemicatenanes. PLoS ONE 2008;3(8):e2855.
[85] Gaillard C, Strauss F. DNA loops and semicatenated DNA junctions. BMC Biochem 2000;1:1.
[86] Angus DC, Yang L, Kong L, Kellum JA, Delude RL, Tracey KJ, et al. Circulating high-mobility group box 1 (HMGBl) concentrations are elevated in both uncomplicated pneumonia and pneumonia with severe sepsis. Crit Care Med 2007 Apr;35(4):1061-7.
[87] 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 Dec 15;170(12):1310- 6.
[88] Nowak P, Barqasho B, Sonnerborg A. Elevated plasma levels of high mobility group box protein 1 in patients with HIV-1 infection. AIDS 2007 Apr 23;21(7):869-71.
[89] Gulick RM, Lalezari J, Goodrich J, Clumeck N, DeJesus E, Horban A, et al. Maraviroc for previously treated patients with R5 HIV-1 infection. N Engl J Med 2008 Oct 2;359(14):1429-41.
[90] Li J, Kokkola R, Tabibzadeh S, Yang R, Ochani M, Qiang X, et al. Structural basis for the proinflammatory cytokine activity of high mobility group box 1. Mol Med 2003 Jan-Feb;9(1-2):37-45.
[91] Telusma G, Datta S, Mihajlov I, Ma W, Li J, Yang H, et al. Dendritic cell activating peptides induce distinct cytokine profiles. Int Immunol 2006 Nov;18(11):1563-73.