Interferon-gamma priming is involved in the activation of arginase by oligodeoxinucleotides containing CpG motifs in murine macrophages

Abstract

Recognition of microbial products by macrophages (Mphi) stimulates an inflammatory response and plays a critical role in directing the host immune response against infection. In the present work, we showed for the first time that synthetic oligodeoxynucleotides containing unmethylated cytosine guanine motifs (CpG) are able to stimulate, in the presence of interferon-gamma (IFN-gamma), both arginase and inducible nitric oxide synthase (iNOS) in murine Mphi. Unexpectedly, IFN-gamma, a cytokine believed to be an inhibitor of arginase activity, intervened in the activation of this enzyme. A significant increase in arginase activity was observed upon a short pre-incubation (1 hr) with IFN-gamma and subsequent CpG stimulation. Therefore, a very interesting observation of this study was that the CpG-mediated arginase activity is dependent on IFN-gamma priming. The increase in arginase activity as a result of stimulation with CpG plus IFN-gamma was correlated with augmented expression of the arginase II isoform. The use of pharmacological specific inhibitors revealed that arginase activity was dependent on p38 mitogen-activated protein kinase (MAPK) and extracellular signal-regulated protein kinase (ERK), but independent of c-Jun N-terminal kinase (JNK) activation. This report reveals a singular effect of the combination of CpG and IFN-gamma, one of the mayor cytokines produced in response to CpG administration in vivo.