UBC Theses and Dissertations

UBC Theses Logo

UBC Theses and Dissertations

Interleukin-10 inhibition of tumor necrosis factor alpha production in activated macrophages requires SHIP1 and Btk Golds, Gary Brandhorst


Inflammation is a physiological process required for defense against pathogens and the repair of damaged tissues. However, excessive or improper inflammation can be detrimental and results in a number of diseases such as rheumatoid arthritis and inflammatory bowel disease. To prevent the negative effects of inflammation, the inflammatory response is tightly regulated by the anti-inflammatory cytokine interleukin-10 (IL-10). The main target of IL-10 are activated macrophages whose exposure to IL-10 results in the anti-inflammatory response (AIR) characterized by depressed antigen presentation and the inhibited secretion of pro-inflammatory cytokines such as tumor necrosis factor alpha (TNFα). To induce the AIR in macrophages, IL-10 binds to cell surface receptors which activate the transcription factor STAT3 leading to the transcription of gene products responsible for carrying out the AIR. However, we hypothesized that IL-10 also uses a STAT3-independent mechanism to induce the AIR. Here we demonstrate that IL-10 utilizes the lipid phosphatase SHIP1 to inhibit TNFα production in activated macrophages. SHIP1 is responsible for dissociating TNFα mRNA from polysomes leading to inhibited translation of TNFα mRNA during the AIR. This effect of SHIP1 occurs early in the AIR and helps to immediately halt TNFα production. We also demonstrate that the tyrosine kinase Btk, a reported positive regulator of TNFα production in macrophages, is also utilized by IL-10 in the early AIR to inhibit TNFα production. However, Btk is not required for IL-10 to dissociate TNFα mRNA from polysomes suggesting that Btk and SHIP1 are involved in distinct IL-10 signalling pathways. Finally we show that TIA-1, a RNA binding protein that silences TNFα mRNA translation is not involved in the IL-10 AIR. These results clearly demonstrate the existence of non-STAT3 signalling pathways in the IL-10 AIR and suggest that SHIP1 and Btk activators could be used as potential therapeutics in the treatment of inflammatory disorders.

Item Media

Item Citations and Data


Attribution-NonCommercial-NoDerivatives 4.0 International