203: IL10 inhibits induction of miR-155 by suppressing Ets2 – A possible mechanism for the anti-inflammatory effects of IL10

MicroRNA-155 (miR-155) is highly expressed in many cancers such as B cell lymphomas and myeloid leukemia, and inflammatory disorders such as rheumatoid arthritis, atopic dermatitis and multiple sclerosis. The role of miR-155 as both a promoter of inflammation and an oncogenic agent provides a clear need for miR-155 itself to be stringently regulated. We have recently found that the immunomodulatory cytokine Interleukin 10 (IL-10) can potently inhibit miR-155 expression in response to stimulation of innate immune signaling pathways. We have found that IL-10 acts by suppressing the Ets family of transcription factors, which are required for miR-155 transcription. We found that IL-10 can act directly to control a number of Ets family members including Ets-2 and its repressor factor, ERF. ChIP assays, in addition to truncation and mutation studies, revealed a key Ets binding site through which IL-10 may act to inhibit miR-155. Inhibition of miR-155 by IL-10 acting via suppression of Ets2 is likely to be part of the molecular mechanism whereby IL-10 elicits its anti-inflammatory and immunomodulatory effects.