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.
OBJECTIVE
The stress protein and endoplasmic reticulum chaperone, immunoglobulin binding protein (BiP), is an autoantigen in rheumatoid arthritis (RA). Stress proteins, however, may have extracellular functions, mediated via cell surface receptors, that may include immunomodulatory functions. We sought to determine whether cell-free BiP is present in the synovial fluid (SF) of patients with RA and to further investigate the possible extracellular antiinflammatory and immunomodulatory properties of BiP in peripheral blood mononuclear cells (PBMCs) in vitro.


METHODS
The presence of BiP in SF was established by Western blotting. PBMCs were stimulated with exogenous recombinant human BiP, and cytokine production and cell proliferation were measured in the presence and absence of cell signaling inhibitors or neutralizing anti-interleukin-10 (anti-IL-10) monoclonal antibody. Cytokine levels were quantified by enzyme-linked immunosorbent assay, cell proliferation by tritiated thymidine uptake, and cell surface molecule expression by flow cytometry.


RESULTS
PBMCs responded to BiP with secretion of an antiinflammatory profile of cytokines. Although BiP stimulated the early production of tumor necrosis factor alpha (TNF alpha), the major cytokine induced was IL-10. Soluble TNF receptor II and IL-1 receptor antagonist secretion was also increased. Addition of SB203580, the MAPK p38 pathway inhibitor, partially inhibited the production of IL-10 and TNF alpha, whereas they were unaffected by the MAPK ERK-1/2 inhibitor PD98059. BiP also inhibited the recall antigen response by PBMCs to tuberculin purified protein derivative. Further investigation showed that incubation of monocytes in the presence of either BiP or IL-10 down-regulated CD86 and HLA-DR expression. The effect observed with IL-10 was transient compared with the long-lasting reduction induced by BiP.


CONCLUSIONS
Extracellular BiP may stimulate immunomodulatory and antiinflammatory pathways, which are only partly due to the production of IL-10. These properties may be of relevance for the treatment of diseases such as RA.
Corrigall
Valerie M
VM
Department of Rheumatology, Guy's, King's, and St. Thomas' School of Medicine, Guy's Hospital, King's College London, London, UK. valerie.corrigal@kcl.ac.uk
Bodman-Smith
Mark D
MD
Brunst
Melanie
M
Cornell
Hannah
H
Panayi
Gabriel S
GS
D000938:Antigen-Presenting Cells / Q000276:immunology* / Q000378:metabolism; D015703:Antigens, CD / Q000378:metabolism; D001172:Arthritis, Rheumatoid / Q000276:immunology* / Q000378:metabolism; D051940:B7-2 Antigen; D002352:Carrier Proteins / Q000378:metabolism*; D002478:Cells, Cultured; D015536:Down-Regulation / Q000276:immunology; D000091342:Endoplasmic Reticulum Chaperone BiP; D005110:Extracellular Space / Q000378:metabolism; D006684:HLA-DR Antigens / Q000378:metabolism; D006360:Heat-Shock Proteins; D006801:Humans; D066298:In Vitro Techniques; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1 / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000276:immunology; D008562:Membrane Glycoproteins / Q000378:metabolism; D018832:Molecular Chaperones / Q000378:metabolism*; D009000:Monocytes / Q000276:immunology* / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D047889:Receptors, Tumor Necrosis Factor, Type II; D012795:Sialoglycoproteins / Q000378:metabolism; D013582:Synovial Fluid / Q000276:immunology / Q000378:metabolism; D014373:Tuberculin / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D015703:Antigens, CD; D051940:B7-2 Antigen; C497964:CD86 protein, human; D002352:Carrier Proteins; D000091342:Endoplasmic Reticulum Chaperone BiP; D006684:HLA-DR Antigens; D006360:Heat-Shock Proteins; C507763:IL1RN protein, human; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D008562:Membrane Glycoproteins; D018832:Molecular Chaperones; D018124:Receptors, Tumor Necrosis Factor; D047889:Receptors, Tumor Necrosis Factor, Type II; D012795:Sialoglycoproteins; D014373:Tuberculin; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10