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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 Apr; 50(4):1164-71.AR

Abstract

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.

CONCLUSION

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.

Authors+Show Affiliations

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.ukNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

15077298

Citation

Corrigall, Valerie M., et al. "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 and Rheumatism, vol. 50, no. 4, 2004, pp. 1164-71.
Corrigall VM, Bodman-Smith MD, Brunst M, et al. 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(4):1164-71.
Corrigall, V. M., Bodman-Smith, M. D., Brunst, M., Cornell, H., & Panayi, G. S. (2004). 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 and Rheumatism, 50(4), 1164-71.
Corrigall VM, et al. 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(4):1164-71. PubMed PMID: 15077298.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Corrigall,Valerie M, AU - Bodman-Smith,Mark D, AU - Brunst,Melanie, AU - Cornell,Hannah, AU - Panayi,Gabriel S, PY - 2004/4/13/pubmed PY - 2004/5/12/medline PY - 2004/4/13/entrez SP - 1164 EP - 71 JF - Arthritis and rheumatism JO - Arthritis Rheum VL - 50 IS - 4 N2 - 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. CONCLUSION: 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. SN - 0004-3591 UR - https://www.unboundmedicine.com/medline/citation/15077298/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_ L2 - https://doi.org/10.1002/art.20134 DB - PRIME DP - Unbound Medicine ER -