Lipopolysaccharide stimulates p38-dependent induction of antiviral genes in neutrophils independently of paracrine factors.

Abstract Lipopolysaccharide (LPS) induces neutrophils to synthesize and secrete pro-inflammatory cytokines and chemokines, which are regulated at both the transcriptional and translational level. We reported previously that neutrophils stimulated with LPS induce expression of genes typically expressed in response to stimulation with antiviral type I interferons (IFN), such as myxovirus resistance-1 (MX1). However, we present evidence that this response of neutrophils to lipopolysaccharide occurs in the absence of interferon-dependent signaling. Lipopolysaccharide-stimulated neutrophils do not phosphorylate the interferon-associated transcription factors signal transducer and activator of transcription-1 and –3, and medium from lipopolysaccharide-stimulated cells was unable to induceMX1 gene expression, suggesting a soluble factor is not involved. Furthermore, LPS did not alter expression of IFNAand IFNB genes. In contrast to neutrophils, LPS-stimulated human monocyte-derived macrophages induced the expression ofMX1, but IFNB was induced, and medium from LPS-stimulated monocyte-derived macrophages supported MX1induction. An inhibitor of p38 kinase blocked induction ofMX1 by lipopolysaccharide, but not IFNα, in neutrophils, and induction of MX1 was dependent on protein synthesis. LPS, but not IFNα, substantially activated p38. In contrast, the induction of MX1 by LPS in monocyte-derived macrophages was insensitive to p38 inhibition, although p38 is phosphorylated in LPS-stimulated but not IFNα-stimulated monocyte-derived macrophages. The expression of MX1 in neutrophils and monocyte-derived macrophages is mediated by TLR4 but not TLR2. The data presented here indicate that lipopolysaccharide activates novel interferon-independent signaling pathways in neutrophils and that induction of antiviral genes is a consequence of exposure of neutrophils to bacterial products.