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

TNFα-induced expression of CD83 in leukocytes is mediated by NF-κb. The aim of our present study was to investigate the underlying mechanism of a unique functional antagonism between GM-CSF and TNFα-induced up-regulation of CD83 in human neutrophils. CD83 was down-regulated by co-stimulation of neutrophils with TNFα and GM-CSF compared to TNFα alone both at the level of mRNA and protein. In marked contrast, the expression of IL-1RA was up-regulated under the same conditions. The down-regulation of CD83 was not mediated by modulation of the NF-κb signaling pathway. Neither was it mediated by a decrease in mRNA stability of CD83. NF-κb was modulated under these conditions as both the expression of the target gene IL-1RA as well as the phosphorylation of IkBα were up-regulated. Our results show that co-stimulation with pro-inflammatory cytokines such as TNFα and GM-CSF can have differential effects on inflammatory pathways initiated in the same target cell. GM-CSF can both synergize with TNFα 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.