Functional antagonism by GM-CSF on TNF-α-induced CD83 expression in human neutrophils

TNF alpha-induced expression of CD83 in leukocytes is mediated by NF-kappa b. The aim of our present study was to investigate the underlying mechanism of a unique functional antagonism between GM-CSF and TNFa-induced up-regulation of CD83 in human neutrophils. CD83 was down-regulated by co-stimulation of neutrophils with TNF alpha and GM-CSF compared to TNF alpha alone both at the level of mRNA and protein. In marked contrast, the expression of IL-1 RA was up-regulated under the same conditions. The down-regulation of CD83 was not mediated by modulation of the NF-kappa b signaling pathway. Neither was it mediated by a decrease in mRNA stability of CD83. NF-kappa b was modulated under these conditions as both the expression of the target gene IL-1 RA as well as the phosphorylation of 1kB alpha were up-regulated. Our results show that co-stimulation with pro-inflammatory cytokines such as TNF alpha and GM-CSF can have differential effects on inflammatory pathways initiated in the same target cell. GM-CSF can both synergize with TNF alpha in the case of expression of IL1-RA and antagonize in the case of CD83. Therefore, expression of CD83 as read out for activation of neutrophils in patients with inflammatory diseases is complicated by the presence of cross-modulating cytokines such as GM-CSF. (C) 2008 Elsevier Ltd. All rights reserved.