A membrane form of TNF-alpha presented by exosomes delays T cell activation-induced cell death.

Abstract

In common with many other cell types, synovial fibroblasts produce exosomes. In this study, we show that the exosomes produced by synovial fibroblasts obtained from individuals with rheumatoid arthritis (RASF), but not exosomes produced by synovial fibroblasts obtained from individuals with osteoarthritis, contain a membrane bound form of TNF-alpha as demonstrated by colloidal gold immunostaining of TNF-alpha and confirmed by both Western blot and mass spectrometry. The RASF-derived exosomes, but not exosomes derived from fibroblasts obtained from individuals with osteoarthritis, are cytotoxic for the L929 cell, a TNF-alpha-sensitive cell line, and stimulate activation of NF-kappaB and induction of collagenase-1 in RASF. These effects are blocked by addition of soluble TNFR1 (sTNFbp), suggesting that a TNF-alpha-signaling pathway mediates these biological activities. sTNFbp also reduced the production of exosomes by RASF, suggesting the interruption of a positive amplification loop. Exosomes can transmit signals between cells, and RASF exosomes, effectively taken up by anti-CD3-activated T cells, activated AKT and NF-kappaB and rendered these activated T cells resistant to apoptosis. Neutralization of exosomal membrane TNF-alpha by sTNFbp partially reversed this resistance, suggesting that not only TNF-alpha but also additional exosomal proteins may contribute to the development of apoptosis resistance.

• Authors: Huang-Ge Zhang, Cunren Liu, Kaihong Su, Kaihun Su, Shaohua Yu, Liming Zhang, Shuangqin Zhang, Jianhua Wang, Xu Cao, William Grizzle, Robert P Kimberly
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 176 Issue 12 Pg. 7385-93 (Jun 15 2006) ISSN: 0022-1767 [Print] United States
• PMID: 16751383 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Membrane Proteins
• Tumor Necrosis Factor-alpha

Topics

• Aged
• Animals
• Antigen Presentation
• Apoptosis (immunology)
• Arthritis, Rheumatoid (immunology, metabolism, pathology)
• Cell Line
• Cell Line, Tumor
• Cell Proliferation
• Coculture Techniques
• Cytotoxicity, Immunologic
• Exocytosis (immunology)
• Female
• Fibroblasts (immunology, metabolism, pathology)
• Humans
• Lymphocyte Activation (immunology)
• Membrane Proteins (immunology, metabolism, physiology)
• Mice
• Middle Aged
• Osteoarthritis (immunology, metabolism, pathology)
• Synovial Membrane (immunology, metabolism, pathology)
• T-Lymphocytes (immunology, metabolism)
• Tumor Necrosis Factor-alpha (immunology, metabolism, physiology)