Mechanisms of double-stranded RNA-induced macrophage activation

Viral infection has been implicated as a triggering mechanism that may initiate the destruction of β-cells during the development of autoimmune diabetes. Macrophages have been shown to be necessary for viral-induced diabetes in animal models. dsRNA is an active component of a viral infection that stimulates the antiviral responses in infected cells. Nitric oxide and IL-1 produced in response to dsRNA by resident islet and inflammatory macrophages may be factors that mediate β-cell dysfunction and eventual β-cell death. The purpose of this study is to elucidate the mechanisms by which dsRNA activates macrophages. We have identified four pathways that are activated in response to dsRNA in macrophages. The first involves PKR and leads to the activation of yet to be identified factor(s), which are necessary for dsRNA-induced iNOS and IL-1 gene activation. The second is a PKR-independent pathway leading to dsRNA-induced NF-κB activation. The factor(s) upstream of NF-κB activated by dsRNA are not yet known. The third pathway activated by dsRNA is initiated by unknown factor(s) and leads to the activation of iPLA ₂. Activation of iPLA₂ leads to PKA activation and both are required for dsRNA-induced iNOS expression. Interestingly this pathway does not regulate dsRNA-induced IL-1 expression. dsRNA-induced IL-1 expression is regulated by the ERK1/2 MAP kinase (the fourth pathway). dsRNA-induced ERK1/2 activity leads to the activation of PU.1, a transcription factor required for IL-1 gene expression.