Skip to main content Accessibility help
  • Get access
    Check if you have access via personal or institutional login
  • Cited by 2
  • Print publication year: 2005
  • Online publication date: August 2009

14 - BiP, a Negative Regulator Involved in Rheumatoid Arthritis



The heat shock protein (Hsp) 70 family is a collection of evolutionarily conserved, ubiquitous proteins that are either constitutively expressed and/or stress induced and which are nominally defined by their molecular weight (Hsp70, Hsc73, BiP (binding immunoglobulin protein, or glucose regulated protein (grp) 78)). Historically, these proteins have been perceived to function as intracellular molecular chaperones that ensure the correct folding of nascent proteins and are involved in the translocation of proteins and assist in protein degradation through the proteasome [1]. At times of physical or chemical stress, such chaperones are upregulated by the unfolded protein response and provide protection against the accumulation and aggregation of denatured proteins.

In contrast to this long-standing perception, there is now increasing interest in an intercellular signalling role for these proteins and, as a consequence, they have been termed ‘chaperokines’ in light of their cytokine-like qualities [2, 3]. The interaction between heat shock proteins and specific cell surface receptors that signal the release of inflammatory mediators has revealed a link between the innate and adaptive immune response. A wide range of extracellular receptors for human Hsp70 has been identified. These include CD14 [2, 4, 5], Toll-like receptor (TLR) 4, TLR2 [4, 6], CD91 [7, 8] and CD40 [9, 10] on monocytes, and scavenger receptors such as LOX-1 on dendritic cells (DCs) [11]. The role of these receptors is detailed in Chapters 7 and 10.

Gething, M J.Role and regulation of the ER chaperone BiP. Semin Cell Dev Biol 1999, 10: 465–472
Asea, A, Kraeft, S-K, Kurt-Jones, E A, Stevenson, M A, Chen, L B, Finberg, R W, Koo, G C and Calderwood, S K.Hsp70 stimulates cytokine production through a CD14-dependent pathway, demonstrating its dual role as a chaperone and cytokine. Nat Med 2000, 6: 435–442
Asea, A, Kabingu, E, Stevenson, M A and Calderwood, S K.HSP70 peptide-bearing and peptide-negative preparations act as chaperokines. Cell Stress Chaperon 2000, 5: 425–431
Kol, A, Lichtman, A H, Finberg, R W, Libby, P and Kurt-Jones, E A.Heat shock protein (HSP) 60 activates the innate immune response: CD14 is an essential receptor for HSP60 activation of mononuclear cells. J Immunol 2000, 164: 13–17
Lewthwaite, J C, Coates, A R M, Tormay, P, Singh, M, Mascagni, P, Poole, S, Roberts, M, Sharp, L and Henderson, B.Mycobacterium tuberculosis chaperonin 60.1 is a more potent cytokine stimulator than chaperonin 60.2 (hsp 65) and contains a CD14-binding domain. Infect Immun 2001, 69: 7349–7355
Asea, A, Rehli, M, Kabingu, E, Boch, J A, Baré, O, Auron, P E, Stevenson, M A and Calderwood, S K.Novel signal transduction pathway utilized by extracellular HSP70. Role of Toll-like receptor (TLR) 2 and TLR4. J Biol Chem 2002, 277: 15028–15034
Basu, S, Binder, R J, Ramalingam, T and Srivastava, P K.CD91 is a common receptor for heat shock proteins gp96, hsp90, hsp70 and calreticulin. Immunity 2001, 14: 303–313
Binder, R J, Han, D K and Srivastava, P K.CD91: a receptor for heat shock protein gp96. Nat Immunol 2000, 1: 151–155
Becker, T, Hartl, F U and Wieland, F. CD40, an extracellular receptor for binding and uptake of Hsp70-peptide complexes. J Cell Biol 2002, 158: 1277–1285
Wang, Y, Kelly, C G, Karttunen, T, Whittall, T, Lehner, P J, Duncan, L, MacAry, P, Younson, J S, Singh, M, Oehlmann, W, Cheng, G, Bergmeier, L and Lehner, T.CD40 is a cellular receptor mediating mycobacterial heat shock protein 70 stimulation of CC-chemokines. Immunity 2001, 15: 971–983
Delneste, Y, Magistrelli, G, Gauchat, J, Haeuw, J, Aubry, J, Nakamura, K, Kawakami-Honda, N, Goetsch, L, Sawamura, T, Bonnefoy, J and Jeannin, P.Involvement of LOX-1 in dendritic cell-mediated antigen cross-presentation. Immunity 2002, 17: 353–362
Habich, C, Baumgart, K, Kolb, H and Burkart, V.The receptor for heat shock protein 60 on macrophages is saturable, specific, and distinct from receptors for other heat shock proteins. J Immunol 2002, 168: 569–576
Matzinger, P. The Danger Model: A renewed sense of self. Science 2002, 296: 301–305
De, A K, Kodys, K M, Yeh, B S and Miller-Graziano, C.Exaggerated human monocyte IL-10 concomitant to minimal TNF-α induction by heat-shock protein 27 (Hsp27) suggests Hsp27 is primarily an anti-inflammatory stimulus. J Immunol 2000, 165: 3951–3958
Haas, I G. BiP (GRP78), an essential hsp70 resident protein in the endoplasmic reticulum. Experientia 1994, 50: 1012–1020
Kozutsumi, Y, Normington, K, Press, E, Slaughter, C, Sambrook, J and Gething, M J.Identification of immunoglobulin heavy chain binding protein as glucose-regulated protein 78 on the basis of amino acid sequence, immunological cross-reactivity, and functional activity. J Cell Sci Suppl 1989, 11: 115–137
Knarr, G, Gething, M J, Modrow, S and Buchner, J.BiP binding sequences in antibodies. J Biol Chem 1995, 270: 27589–27594
Janson, I M, Toomik, R, O'Farrell, F and Ek, P.KDEL motif interacts with a specific sequence in mammalian erd2 receptor. Biochem Biophys Res Commun 1998, 247: 447–451
Kozutsumi, Y, Segal, M, Normington, K, Gething, M J and Sambrook, J.The presence of malfolded proteins in the endoplasmic reticulum signals the induction of glucose-regulated proteins. Nature 1988, 332: 462–464
Mapp, P I, GrootveldM, C M, C, and Blake, D R.Hypoxia, oxidative stress and rheumatoid arthritis. Br Med Bull 1995, 51: 419–436
Tak, P P, Zvaifler, N J, Green, D R and Firestein, G S.Rheumatoid arthritis and p53: how oxidative stress might alter the course of inflammatory diseases. Immunol Today 2000, 21: 78–82
Maurice, M M, Nakamura, H, Voort, E A, Vliet, A I, Staal, F J, Tak, P P, Breedveld, F C and Verweij, C L.Evidence for the role of an altered redox state in hyporesponsiveness of synovial T cells in rheumatoid arthritis. J Immunol 1997, 158: 1458–1465
Blass, S, Union, A, Raymackers, J, Schumann, F, Ungethum, U, Muller-Steinbach, S, Keyser, F, Engel, J M and Burmester, G R.The stress protein BiP is overexpressed and is a major B and T cell target in rheumatoid arthritis. Arthritis Rheum 2001, 44: 761–771
Delpino, A and Castelli, M.The 78 kDa glucose-regulated protein (GRP78/BIP) is expressed on the cell membrane, is released into cell culture medium and is also present in human peripheral circulation. Biosci Reports 2002, 22: 407–420
Gagnon, E, Duclos, S, Rondeau, C, Chevet, E, Cameron, P H, Steele-Mortimer, O, Paiement, J, Bergeron, J J and Desjardins, M.Endoplasmic reticulum-mediated phagocytosis is a mechanism of entry into macrophages. Cell Biol Int 2002, 110: 119–131
Shin, B K, Wang, H, Yim, A M, Naour, F, Brichory, F, Jang, J H, Zhao, R, Puravs, E, Tra, J, Michael, C W, Misek, D E and Hanash, S M.Global profiling of the cell surface proteome of cancer cells uncovers an abundance of proteins with chaperone function. J Biol Chem 2003, 278: 7607–7616
Barreto, A, Gonzalez, J M, Kabingu, E, Asea, A and Fiorentino, S.Stress-induced release of HSC70 from human tumors. Cell Immunol 2003, 222: 97–104
Dai, J, Liu, B, Caudill, M, Zheng, H, Qiao, Y, Podack, E R and Li, Z.Cell surface expression of heat shock protein gp96 enhances cross-presentation of cellular antigens and the generation of tumor-specific T cell memory. Cancer Immun 2003, 3: 1–5
Lewthwaite, J, Owen, N, Coates, A, Henderson, B and Steptoe, A.Circulating human heat shock protein 60 in the plasma of British civil servants. Circulation 2002, 106: 196–201
Habich, C, Kempe, K, Zee, R, Burkart, V and Kolb, H.Different heat shock protein 60 species share pro-inflammatory activity but not binding sites on macrophages. FEBS Lett 2003, 533: 105–109
Wassenberg, J J, Dezfulian, C and Nicchitta, C V.Receptor mediated and fluid phase pathways for internalization of the ER Hsp90 chaperone grp94 in murine macrophages. J Cell Sci 1999, 112: 2167–2175
Binder, R J, Harris, M L, Ménoret, A and Srivastava, P K.Saturation, competition, and specificity in interaction of heat shock proteins (hsp) gp96, hsp90, and hsp70 with CD11b+ cells. J Immunol 2000, 165: 2582–2587
Arnold-Schild, D, Hanau, D, Spehner, D, Schmid, C, Rammensee, H-G, Salle, H and Schild, H.Receptor-mediated endocytosis of heat shock proteins by professional antigen-presenting cells. J Immunol 1999, 162: 3757–3760
Corrigall, V M, Bodman-Smith, M D, Fife, M S, Canas, B, Myers, L K, Wooley, P, Soh, C, Staines, N A, Pappin, D J, Berlo, S E, Eden, W, Zee, R, Lanchbury, J S and Panayi, G S.The human endoplasmic reticulum molecular chaperone BiP is an autoantigen for rheumatoid arthritis and prevents the induction of experimental arthritis. J Immunol 2001, 166: 1492–1498
Brownlie, R, Sattar, Z, Corrigall, V M, Bodman-Smith, M D, Panayi, G S and Thompson, S.Immunotherapy of collagen induced arthritis with BiP. Rheumatology (Oxford) 2003, 42 suppl: 13
Sattar, Z, Brownlie, R, Corrigall, V M, Bodman-Smith, M D, Staines, N A, Panayi, G S et al. CD4+ T cells specific for the stress protein BiP modulate the development of collagen induced arthritis. Rheumatology (Oxford) 2003, 42 suppl: 124
Bodman-Smith, M D, Corrigall, V M, Kemeny, D M and Panayi, G S.BiP, a putative autoantigen in rheumatoid arthritis, stimulates IL-10-producing CD8+ T cells from normal individuals. Rheumatology (Oxford) 2003, 42: 637–644
Krakauer, T. Differential inhibitory effects of interleukin-10, interleukin-4, and dexamethasone on staphylococcal enterotoxin-induced cytokine production and T cell activation. J Leuk Biol 1995, 57: 450–454
Corrigall, V M, Garyfallos, A and Panayi, G S.The relative proportions of secreted interleukin-2 and interleukin-10 determine the magnitude of rheumatoid arthritis T-cell proliferation to the recall antigen tuberculin purified protein derivative. Rheumatology (Oxford) 1999, 38: 1203–1207
Corrigall, V M, Bodman-Smith, M D, Brunst, M, Cornell, H and Panayi, G S.Inhibition of antigen-presenting cell function and stimulation of human peripheral blood mononuclear cells to express an antiinflammatory cytokine profile by the stress protein BiP: relevance to the treatment of inflammatory arthritis. Arthritis Rheum 2004, 50: 1164–1171
Schebesch, C, Kodelja, V, Muller, C, Hakij, N, Bisson, S, Orfanos, C E and Goerdt, S.Alternatively activated macrophages actively inhibit proliferation of peripheral blood lymphocytes and CD4+ T cells in vitro. Immunology 1997, 92: 478–486
Castellino, F, Boucher, P E, Eichelberg, K, Mayhew, M, Rothman, J E, Houghton, A N and Germain, R N.Receptor-mediated uptake of antigen/heat shock protein complexes results in major histocompatibility complex class I antigen presentation via two distinct pathways. J Exp Med 2000, 191: 1957–1964
Gordon, S. Alternative activation of macrophages. Nat Rev Immunol 2003, 3: 23–35
Vittecoq, O, Corrigall, V M, Bodman-Smith, M D and Panayi, G S.The molecular chaperone BiP (GRP78) inhibits the differentiation of normal human monocytes into immature dendritic cells. Rheumatology (Oxford) 2003, 42 suppl: 43
Flohé, S B, Bruggemann, J, Lendemans, S, Nikulina, M, Meierhoff, G, Flohé, S and Kolb, H.Human heat shock protein 60 induces maturation of dendritic cells versus a Th1-promoting phenotype. J Immunol 2003, 170: 2340–2348