T-cell contact-dependent regulation of CC and CXC chemokine production in monocytes through differential involvement of NFkappaB: implications for rheumatoid arthritis.
We and others have reported that rheumatoid arthritis (RA) synovial T cells can activate human monocytes/macrophages in a contact-dependent manner to induce the expression of inflammatory cytokines, including tumour necrosis factor alpha (TNFalpha). In the present study we demonstrate that RA synovial T cells without further activation can also induce monocyte CC and CXC chemokine production in a contact-dependent manner. The transcription factor NFkappaB is differentially involved in this process as CXC chemokines but not CC chemokines are inhibited after overexpression of IkappaBalpha, the natural inhibitor of NFkappaB. This effector function of RA synovial T cells is also shared by T cells activated with a cytokine cocktail containing IL-2, IL-6 and TNFalpha, but not T cells activated by anti-CD3 cross-linking that mimics TCR engagement. This study demonstrates for the first time that RA synovial T cells as well as cytokine-activated T cells are able to induce monocyte chemokine production in a contact-dependent manner and through NFkappaB-dependent and NFkappaB-independent mechanisms, in a process influenced by the phosphatidyl-inositol-3-kinase pathway. Moreover, this study provides further evidence that cytokine-activated T cells share aspects of their effector function with RA synovial T cells and that their targeting in the clinic has therapeutic potential.
Beech
Jonathan T
JT
Kennedy Institute of Rheumatology Division, Imperial College School of Medicine, 1 Aspenlea Road, Hammersmith, London W6 8LH, UK. j.beech@ic.ac.uk
Andreakos
Evangelos
E
Ciesielski
Cathleen J
CJ
Green
Patricia
P
Foxwell
Brian M J
BM
Brennan
Fionula M
FM
D001172:Arthritis, Rheumatoid / Q000276:immunology / Q000378:metabolism*; D017252:CD3 Complex / Q000378:metabolism; D002450:Cell Communication / Q000502:physiology; D019742:Chemokines, CC / Q000096:biosynthesis*; D019743:Chemokines, CXC / Q000096:biosynthesis*; D018920:Coculture Techniques; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D008213:Lymphocyte Activation / Q000502:physiology; D008262:Macrophage Activation / Q000502:physiology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism*; D016328:NF-kappa B / Q000276:immunology / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D013583:Synovial Membrane / Q000166:cytology / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism*
D017252:CD3 Complex; D019742:Chemokines, CC; D019743:Chemokines, CXC; D016328:NF-kappa B; D019869:Phosphatidylinositol 3-Kinases; D051550:I-kappa B Kinase