TNF-induced superoxide anion production in adherent human neutrophils involves both the p55 and p75 TNF receptor.
TNF, a potent activator of neutrophil granulocytes, acts via two cell-surface receptors: the p55-TNF receptor (TNF-R55) and the p75-TNF receptor (TNF-R75), which can be cleaved from the cell surface and thus form soluble TNF-binding proteins (TNF-BP). The role of the two receptors in activation of the neutrophil respiratory burst was investigated. Two mAbs reacting with TNF-R55 (H398 and TBP2) induced O2 release in a similar manner but to a lesser extent than TNF. TBP2, however, required preincubation at 4 degrees C to exert its effect. Preincubation of neutrophils (both at 4 and 37 degrees C) with mAb to TNF-R75 decreased TNF-induced superoxide anion production by 67 and 64%, respectively, indicating the essential role also for TNF-R75 in neutrophil activation. This inhibitory effect could not be explained by cross-down-regulation of TNF-R55 because the TNF-R75 mAb had no effect on TNF binding to TNF-R55 as determined by binding of 125I-labeled TNF or release of TNF-R55-BP as measured by ELISA. Furthermore, the TNF-R75 mAb did not decrease superoxide anion generation induced by the TNF-R55 mAb H398, thus ruling out that the inhibitory effect of the TNF-R75 mAb is due to inhibition of the signaling pathway downstream of TNF-R55. In contrast to the TNF-R75 mAb, TNF-R55 mAbs induced down-regulation of TNF-R75 and shedding of both TNF-R55-BP and TNF-R75-BP. We conclude that both TNF-R55 and TNF-R75 are involved in TNF-induced activation of the neutrophil respiratory burst.
Richter
J
J
Department of Medicine, University Hospital, Lund, Sweden.
Gullberg
U
U
Lantz
M
M
D000911:Antibodies, Monoclonal; D002352:Carrier Proteins / Q000378:metabolism; D002448:Cell Adhesion; D015536:Down-Regulation; D006801:Humans; D066298:In Vitro Techniques; D008970:Molecular Weight; D018375:Neutrophil Activation / Q000187:drug effects*; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism*; D018124:Receptors, Tumor Necrosis Factor / Q000737:chemistry / Q000502:physiology*; D047888:Receptors, Tumor Necrosis Factor, Type I; D016897:Respiratory Burst / Q000187:drug effects; D013481:Superoxides / Q000378:metabolism*; D053319:Tumor Necrosis Factor Decoy Receptors; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D000911:Antibodies, Monoclonal; D002352:Carrier Proteins; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D053319:Tumor Necrosis Factor Decoy Receptors; D014409:Tumor Necrosis Factor-alpha; D013481:Superoxides; C069521:recombinant human tumor necrosis factor-binding protein-1