Expression and function of MIP-2 are reduced by dexamethasone treatment in vivo

Abstract

1. The objective of this study was to examine the effect of dexamethasone on tumour necrosis factor-α (TNF-α)-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 skirt of C57/B16 mice. 2. Initially, we examined the dose-response (0.01-0.5 μg ml-1) and kinetics (0-24 h) of TNF-α-induced leukocyte accumulation. The cellular response was maximal at 0.1 μg ml-1 of TNF-α 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-α-induced recruitment of neutrophils by 87%. Administration of dexamethasone had no effect on the expression of CD18 on neutrophils. 4. TNF-α (0.1 μg 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-α (0.1 μg 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 μg 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-α-induced neutrophil recruitment by inhibiting both the expression and function of MIP-2 in vivo.