The Role of Phosphoinositide 3-Kinase Signaling in Intestinal Inflammation
Figure 2
(a). PI3-kinase/AKT/GSK3β pathway control of pro- and anti-inflammatory cytokine production in innate immune cells determines the balance of Th1 and Th2 immune responses. Plextrin homology (PH) domain containing kinases, PDK, and AKT are recruited to the plasma membrane and bind to PIP3. PDK phosphorylates AKT on Thr308 in the activation loop, and this is followed by Ser473 phosphorylation. For MyD88-dependent signaling, TLR-mediated inhibition of GSK3, via AKT phosphorylation of its Ser 9 residue leads to increases in DNA binding of cAmp response element binding protein 1 (CREB), which displaces the coactivator CBP from NFB. The increased CREB activity leads to production of the anti-inflammatory cytokine IL-10 (Th2 cytokine) and lowered IL-12 production. Inhibition of PI3-K via dephosphorylation of PIP3 by the phosphatase PTEN enables GSK3 to remain active to inhibit transcription factors such as cJun and CREB thereby decreasing IL-10, increasing NFB-mediated IL-12 expression, and enhancing Th1 responses. (b) lamina propria T (LPT) cells are hyporesponsive to TCR stimulation and use the alternative CD-2 pathway. PI3-kinase AKT/GSK3β pathway downstream of CD-2 likely targets the AP-1 and NFAT sites on the IL-2 promoter. The activity of the PIP3 phosphatase, PTEN is likely reduced in LPT cells due to the increased thioredoxin (TrX1) in these cells. Multiple TCR stimulation of LPT cells has been reported to induce FOXP3/IL-10 producing immunosuppressive Treg cells [21]. (c) PI3-kinase-dependent pathways to IL-6 gene transcription in response to IL-1 in Caco-2 intestinal epithelial cells. IL-1 binding to the IL-1R1 increases its affinity for the co-receptor, the IL-1 receptor accessory protein (IL-1RAcP). Formation of the signaling module containing the MyD88 adaptor protein together with phosphorylated IRAK (interleukin-1 receptor-associated kinase) and TRAF-6 (TNF receptor-associated factor) is essential for PI3-K recruitment and AKT activation. The TAK1 (TGFβ activated kinase) signaling module is likely a separate parallel pathway to NFB activation. We identified 2 separate pathways to the induction of IL-6 transcription in response to IL-1, the first is a novel IKKα-dependent pathway involving phosphorylation of the T23 residue on IKKα, upstream of AP-1 (activator protein 1) activation, and the second is an AKT-dependent activation of NFB, likely via phosphorylation of the p65 subunit [22].
