Redundant function of macrophage inflammatory protein-2 and KC in tumor necrosis factor-alpha-induced extravasation of neutrophils in vivo.
Tumor necrosis factor-alpha (TNF-alpha) stimulates the expression CXC chemokines, i.e. macrophage inflammatory protein-2 (MIP-2) and cytokine-induced neutrophil chemoattractant (KC), and neutrophil extravasation. However, the individual role of MIP-2 and KC in the recruitment process of neutrophils in vivo remains elusive. By use of intravital microscopy in the mouse cremaster muscle, we analyzed the effect of specific inhibition of CXC chemokines, alone and together, on TNF-alpha-induced leukocyte rolling, firm adhesion and recruitment. After stimulation with TNF-alpha, the mRNA levels of both MIP-2 and KC were increased. Notably, separate administration of antibodies directed against MIP-2 and KC had no effect on TNF-alpha-induced neutrophil extravasation. In contrast, combined injection of anti-MIP-2 and anti-KC antibodies markedly inhibited extravascular migration of neutrophils. Moreover, MIP-2 and KC dose-dependently increased neutrophil recruitment, however, no synergistic effect of combined stimulation with MIP-2 and KC on the neutrophil response was found. Taken together, these data suggest that MIP-2 and KC are functionally redundant in TNF-alpha-induced neutrophil accumulation and that neutralization of both MIP-2 and KC may be necessary in order to reduce accumulation of neutrophils in cytokine-activated tissues.
Zhang
X W
XW
Department of Surgery, Malmö University Hospital, Lund University, 20502 Malmö, Sweden.
Wang
Y
Y
Liu
Q
Q
Thorlacius
H
H
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001783:Blood Flow Velocity / Q000187:drug effects; D002199:Capillary Permeability / Q000187:drug effects; D054426:Chemokine CXCL2; D018925:Chemokines / Q000235:genetics / Q000276:immunology / Q000494:pharmacology*; D002630:Chemotactic Factors / Q000235:genetics / Q000276:immunology / Q000494:pharmacology*; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004912:Erythrocytes / Q000187:drug effects / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects; D007958:Leukocyte Count; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018482:Muscle, Skeletal / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism; D020556:Neutrophil Infiltration / Q000187:drug effects; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects*; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D051381:Rats; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D000911:Antibodies, Monoclonal; D054426:Chemokine CXCL2; D018925:Chemokines; D002630:Chemotactic Factors; C404915:Cxcl2 protein, mouse; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha