Inflammation research : official journal of the European Histamine Research Society ... [et al.] · 2019
ER stress abrogates the immunosuppressive effect of IL-10 on human macrophages through inhibition of STAT3 activation.
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Hansen Ivo S, Schoonejans Josca M, Sritharan Lathees, van Burgsteden Johan A, Ambarus Carmen A, Baeten Dominique L P, den Dunnen Jeroen
Аннотация
OBJECTIVE AND DESIGN: To determine whether ER stress affects the inhibitory pathways of the human immune system, particularly the immunosuppressive effect of IL-10 on macrophages.
MATERIAL OR SUBJECTS: In vitro stimulation of human monocyte-derived macrophages.
TREATMENT: Cells were stimulated with TLR ligands and IL-10, while ER stress was induced using thapsigargin or tunicamycin.
METHODS: mRNA expression was determined using qPCR, while cytokine protein production was measured using ELISA. Protein expression of receptors and transcription factors was determined using flow cytometry. Student's t test was used for statistics.
RESULTS: While under normal conditions IL-10 potently suppresses pro-inflammatory cytokine production by LPS-stimulated macrophages, we demonstrate that ER stress counteracts the immunosuppressive effects of IL-10, leading to increased pro-inflammatory cytokine production. We identified that ER stress directly interferes with IL-10R signaling by reducing STAT3 phosphorylation on Tyr705, which thereby inhibits the expression of SOCS3. Moreover, we show that ER stress also inhibits STAT3 activation induced by other receptors such as IL-6R.
CONCLUSIONS: Combined, these data uncover a new general mechanism by which ER stress promotes inflammation. Considering its potential involvement in the pathogenesis of diseases such as Crohn's disease and spondyloarthritis, targeting of this mechanism may provide new opportunities to counteract inflammation.
MATERIAL OR SUBJECTS: In vitro stimulation of human monocyte-derived macrophages.
TREATMENT: Cells were stimulated with TLR ligands and IL-10, while ER stress was induced using thapsigargin or tunicamycin.
METHODS: mRNA expression was determined using qPCR, while cytokine protein production was measured using ELISA. Protein expression of receptors and transcription factors was determined using flow cytometry. Student's t test was used for statistics.
RESULTS: While under normal conditions IL-10 potently suppresses pro-inflammatory cytokine production by LPS-stimulated macrophages, we demonstrate that ER stress counteracts the immunosuppressive effects of IL-10, leading to increased pro-inflammatory cytokine production. We identified that ER stress directly interferes with IL-10R signaling by reducing STAT3 phosphorylation on Tyr705, which thereby inhibits the expression of SOCS3. Moreover, we show that ER stress also inhibits STAT3 activation induced by other receptors such as IL-6R.
CONCLUSIONS: Combined, these data uncover a new general mechanism by which ER stress promotes inflammation. Considering its potential involvement in the pathogenesis of diseases such as Crohn's disease and spondyloarthritis, targeting of this mechanism may provide new opportunities to counteract inflammation.