Abstract
There remains a significant need for development of effective small molecules that can inhibit cytokine-mediated inflammation. Phosphoinositide 3 kinase (PI3K) is a direct upstream activator of AKT, and plays a critical role in multiple cell signaling pathways, cell cycle progression, and cell growth, and PI3K inhibitors have been approved or are in clinical development. We examined novel PI3Kdelta inhibitors, which are highly selective for the p110delta isoform of in CD3/CD28 stimulated T-cell cytokine production. In vitro generated CD4+ T effector cells stimulated in the presence of a PI3Kdelta inhibitor demonstrated a dose-dependent suppression of cytokines produced by Th1, Th2, and Th17 cells. This effect was T-cell intrinsic, and we observed similar effects on human PBMCs. Th17 cells expressing a constitutively activated form of AKT were resistant to PI3Kdelta inhibition, suggesting that the inhibitor is acting through AKT signaling pathways. Additionally, PI3Kdelta inhibition decreased IL-17 production in vivo and decreased neutrophil recruitment to the lung in a murine model of acute pulmonary inflammation. These experiments show that targeting PI3Kdelta activity can modulate T-cell cytokine production and reduce inflammation in vivo, suggesting that PI3Kdelta inhibition could have therapeutic potential in treating inflammatory diseases.
Highlights
The immunologic pathways that lead to inflammation are extremely complex and are, in many cases, incompletely understood
It has been established by others that inhibition of PI3Kδ results in suppression of T helper 17 (Th17) cell differentiation and function and can alleviate inflammation in human and animal models[24,25,26,27]
We analyzed the ability of a selective PI3Kδ inhibitor, Compound A, to inhibit IL-17 production from Th17 cells in vitro
Summary
The immunologic pathways that lead to inflammation are extremely complex and are, in many cases, incompletely understood. Inflammatory pathways involving T helper 17 (Th17) cells have become a particular therapeutic target of interest since their discovery, as these cells have been found to play a vital role in autoimmune and inflammatory conditions, as well as infection[1,2]. PI3K is an enzyme which uses cell membrane lipids to produce second messengers that are involved in numerous cellular functions including growth, survival, protein synthesis, and metabolism[13,14]. PI3Kδ, in particular, plays a critical role in the differentiation process of naïve T cells into effector T helper subsets[14,15,20], which makes it a strong candidate as a therapeutic target for drug development. There has been marked growth in the development of PI3K inhibitors, though most of these compounds have been aimed at cancer treatment due to the high frequency of dysregulation with this pathway in tumorigenesis[21,22,23]
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