Anti-inflammatory action of insulin via induction of Gadd45-β transcription by the mTOR signaling pathway

Katherine D Bortoff¹, Adam B Keeton¹, J Lee Franklin¹, Joseph L Messina^1,2

¹Department of Pathology, Division of Molecular and Cellular Pathology, The University of Alabama at Birmingham, Birmingham, Alabama, USA; ²Veterans Affairs Medical Center, Birmingham, Alabama, USA

Abstract: Insulin regulates a large number of genes in a tissue-specific manner. We have previously identified genes modulated by insulin in the liver and in liver-derived cells that have not yet been characterized as insulin regulated, and results of these previous studies indicated that numerous genes are induced by insulin via the MEK-ERK pathway. We now describe new studies indicating that Gadd45-β can be induced by acute insulin treatment. Although other regulators of Gadd45-β expression may utilize the MEK-ERK pathway, the data indicate that insulin utilizes signaling pathways separate from either MEK-ERK, PI3-K, or p38 signaling pathways in the regulation of Gadd45-β transcription. Our findings show that activation of a downstream effector of multiple signaling pathways, mTOR, was required for insulin-induction of Gadd45-β gene transcription. Increased expression of Gadd45-β can inhibit c-Jun N-terminal kinase (JNK) activity. Since TNFα is increased during inflammation, and acts, at least in part, via the JNK signaling pathway, insulin induction of Gadd45-β suggests a mechanism for the anti-inflammatory actions of insulin.

Keywords: insulin, Gadd45−β, mTOR, ERK, PI3-kinase, p38, JNK