ABSTRACT
Although B cells have been shown to contribute to the pathogenesis of rheumatoid arthritis (RA), the precise role of B cells in RA needs to be explored further. Our previous studies have revealed that adiponectin (AD) is expressed at high levels in inflamed synovial joint tissues, and its expression is closely correlated with progressive bone erosion in patients with RA. In this study, we investigated the possible role of AD in B cell proliferation and differentiation. We found that AD stimulation could induce B cell proliferation and differentiation in cell culture. Notably, local intraarticular injection of AD promoted B cell expansion in joint tissues and exacerbated arthritis in mice with collagen-induced arthritis (CIA). Mechanistically, AD induced the activation of PI3K/Akt1 and STAT3 and promoted the proliferation and differentiation of B cells. Moreover, STAT3 bound to the promoter of the Blimp-1 gene, upregulated Blimp-1 expression at the transcriptional level, and promoted B cell differentiation. Collectively, we observed that AD exacerbated CIA by enhancing B cell proliferation and differentiation mediated by the PI3K/Akt1/STAT3 axis.
Subject(s)
Adiponectin/toxicity , Arthritis, Experimental/enzymology , B-Lymphocytes/drug effects , Cell Differentiation/drug effects , Cell Proliferation/drug effects , Lymphocyte Activation/drug effects , Proto-Oncogene Proteins c-akt/metabolism , STAT3 Transcription Factor/metabolism , Animals , Arthritis, Experimental/chemically induced , Arthritis, Experimental/immunology , Arthritis, Experimental/pathology , B-Lymphocytes/enzymology , B-Lymphocytes/immunology , Collagen Type II , Enzyme Activation , Male , Mice, Inbred C57BL , Mice, Inbred DBA , Phosphatidylinositol 3-Kinase/metabolism , Positive Regulatory Domain I-Binding Factor 1/genetics , Positive Regulatory Domain I-Binding Factor 1/metabolism , Proto-Oncogene Proteins c-akt/genetics , Receptors, Adiponectin/agonists , Receptors, Adiponectin/genetics , Receptors, Adiponectin/metabolism , STAT3 Transcription Factor/genetics , Signal TransductionABSTRACT
PURPOSE: Various proapoptotic agents are currently being explored to improve the outcome of radiotherapy. We have evaluated whether APO010-a novel recombinant ligand of the Fas/CD95 death receptor-enhanced the cytotoxic effect of radiation on lymphoid and solid tumor cell types. EXPERIMENTAL DESIGN: A Bcl-2-overexpressing T-leukemic cell line (Jurkat), a colon carcinoma cell line (HCT116), and a mesothelioma cell line were used as model systems in vitro and in a subcutaneous transplant setting in immunodeficient mice. Sensitivity to single and combined treatment was read out by apoptosis hallmarks and clonogenic survival in vitro, and by tumor growth delay using bioluminescence and palpation in vivo. RESULTS: Whereas the three cell lines resisted apoptosis induction by irradiation and APO010 alone, combined treatment greatly enhanced their apoptotic response. In clonogenic survival assays, APO010 reduced the outgrowth of Jurkat-Bcl-2 and HCT116 cells and sensitized the mesothelioma cell line to radiation. In vivo, systemic treatment with APO010 alone caused tumor growth delay in Jurkat-Bcl-2 and HCT116 cells. However, APO010 did not improve the efficacy of radiotherapy in any of the model systems at the selected single dose, which had moderate and reversible systemic toxicity. CONCLUSIONS: Although APO010 and radiation had a clear combined cytotoxic effect on tumor cells in vitro, a combined therapeutic effect was not achieved on the same cells subcutaneously grafted in mice, at APO010 doses approximating the maximally tolerable level. These findings suggest that it will be difficult to identify a therapeutic window for this combined modality approach in a clinical setting.
