Expression and function of MIP-2 are reduced by dexamethasone treatment in vivo.
1. The objective of this study was to examine the effect of dexamethasone on tumour necrosis factor-alpha (TNF-alpha)-induced expression and function of macrophage inflammatory protein-2 (MIP-2) and neutrophil recruitment. For this purpose, we used air pouches raised on the dorsal skin of C57/B16 mice. 2. Initially, we examined the dose-response (0.01 - 0.5 microg ml(-1)) and kinetics (0 - 24 h) of TNF-alpha-induced leukocyte accumulation. The cellular response was maximal at 0.1 microg ml(-1) of TNF-alpha and 4 h after challenge and comprised more than 90% neutrophils. 3. Intraperitoneal (i.p.) pretreatment with 10 mg kg(-1) of dexamethasone for 2 h, but not 1 mg kg(-1), reduced TNF-alpha-induced recruitment of neutrophils by 87%. Administration of dexamethasone had no effect on the expression of CD18 on neutrophils. 4. TNF-alpha (0.1 microg ml(-1)) markedly increased the levels of MIP-2 in the air pouches 1 h after challenge and after 4 h the MIP-2 values returned to baseline. Notably, 2 h pretreatment with dexamethasone (10 mg kg(-1), i.p.) reduced MIP-2 expression by 65% in response to TNF-alpha (0.1 microg ml(-1)). On the other hand, dexamethasone treatment did not change the levels of interleukin-10 (IL-10) in the pouch exudate. 5. Administration of recombinant MIP-2 increased neutrophil accumulation at 0.5 and 1.0 microg ml(-1) after 4 h of challenge. Dexamethasone pretreatment for 2 h (10 mg kg(-1), i.p.) abolished the MIP-2-induced recruitment of neutrophils. 6. Taken together, our data demonstrate that dexamethasone may downregulate TNF-alpha-induced neutrophil recruitment by inhibiting both the expression and function of MIP-2 in vivo.
Schramm
R
R
Department of Surgery, Malmö University Hospital, Lund University, 20502 Malmö, Sweden.
Liu
Q
Q
Thorlacius
H
H
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D018821:CD18 Antigens / Q000096:biosynthesis; D002465:Cell Movement / Q000187:drug effects; D054426:Chemokine CXCL2; D018925:Chemokines / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D003907:Dexamethasone / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects; D016753:Interleukin-10 / Q000096:biosynthesis; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D000893:Anti-Inflammatory Agents; D018821:CD18 Antigens; D054426:Chemokine CXCL2; D018925:Chemokines; C404915:Cxcl2 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D003907:Dexamethasone