Anti-B7-1/B7-2 antibody elicits innate-effector responses in macrophages through NF-kappaB-dependent pathway.
Blocking T cell co-stimulatory signals by anti-B7-1/B7-2 mAb is an attractive approach to treat autoimmune diseases. However, anti-B7-1/B7-2 mAb treatment is known to exacerbate autoimmune diseases through mechanisms not fully understood. Tumor necrosis factor alpha (TNF-alpha) and reactive oxygen species (ROS) also play important roles in determining the clinical outcome of autoimmune diseases. In this study, we demonstrate that the anti-B7-1 and the anti-B7-2 mAbs activate macrophages for higher induction of TNF-alpha and other effector responses such as bacterial cytotoxicity and production of ROS. Nuclear factor-kappaB (NF-kappaB) was found to be increased with anti-B7-1/B7-2 mAb treatment. Inhibition of NF-kappaB activity by over-expression of phosphorylation-defective I-kappaB alpha in anti-B7-1/B7-2 mAb-treated macrophages decreased TNF-alpha production. These data indicate that anti-B7-1 and anti-B7-2 mAbs can trigger innate-effector responses in macrophages by activating NF-kappaB-signaling pathway. Our results suggest that the B7 molecules are not only essential for induction of adaptive immune responses but also play roles in activation of innate immune responses.
Khan
Nooruddin
N
Laboratory of Molecular Cell Biology Center for DNA Fingerprinting and Diagnostics, Hyderabad, India.
Ghousunnissa
Sheikh
S
Jegadeeswaran
SenthilKumar M
SM
Thiagarajan
Dorairajan
D
Hasnain
Seyed E
SE
Mukhopadhyay
Sangita
S
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology*; D018122:B7-1 Antigen / Q000276:immunology* / Q000378:metabolism; D051940:B7-2 Antigen / Q000276:immunology* / Q000378:metabolism; D002460:Cell Line; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D017077:Culture Media, Conditioned / Q000494:pharmacology; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D004926:Escherichia coli / Q000166:cytology / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects; D020672:I-kappa B Proteins / Q000235:genetics; D007113:Immunity, Innate / Q000187:drug effects* / Q000276:immunology; D007140:Immunoglobulin Fab Fragments / Q000494:pharmacology; D007371:Interferon-gamma / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D050296:Microbial Viability / Q000187:drug effects; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
D000911:Antibodies, Monoclonal; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D017077:Culture Media, Conditioned; D020672:I-kappa B Proteins; D007140:Immunoglobulin Fab Fragments; D008070:Lipopolysaccharides; D016328:NF-kappa B; C000606205:Nfkbia protein, mouse; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D000072000:NF-KappaB Inhibitor alpha; D007371:Interferon-gamma