Ruxolitinib is a
Janus kinase (JAK) 1/2 inhibitor, currently used in the treatment of myeloproliferative
neoplasms. It exerts potent anti-inflammatory activity, but the involved molecular and cellular mechanisms remain poorly understood. In order to gain insights about this point,
ruxolitinib effects towards expression of main inflammatory
cytokines were studied in human macrophages, which constitute a key-cell type implicated in
inflammation. Analysis of
mRNA expression of
cytokines (n=84) by PCR array indicated that, among those induced by the pro-inflammatory stimulus
lipopolysaccharide (LPS) (n=44), 61.4% (n=27) were repressed by 5μM
ruxolitinib. The major inflammatory
cytokines,
interleukin (IL) 6 and
tumor necrosis factor α, were notably down-regulated by
ruxolitinib at both the
mRNA and
protein level. Other repressed
cytokines included
IL27 and the
chemokines CCL2, CXCL9, CXCL10 and CXCL11, but not IL1β. The
interferon (IFN) β/JAK/signal transducer and activator of transcription (STAT) pathway, well-activated by LPS in human macrophages as demonstrated by increased secretion of IFNβ, STAT1 phosphorylation, and up-regulation of reference IFNβ-responsive genes, was concomitantly blocked by the
JAK inhibitor. Most of
cytokines targeted by
ruxolitinib were shown to be regulated by IFNβ in a JAK-sensitive manner. In addition, counteracting the IFNβ/JAK/STAT cascade using a blocking
monoclonal antibody directed against IFNβ receptor resulted in a similar profile of
cytokine repression to that observed in response to the
JAK inhibitor. Overall, these data provide evidence for
ruxolitinib-mediated repression of inflammatory
cytokines in human macrophages through inhibition of the LPS/IFNβ/JAK/STAT signalling pathway, which probably contributes to the anti-inflammatory effects of the
JAK inhibitor.