Novel Pharmacological Approaches for Inflammatory Bowel Disease: Targeting Key Intracellular Pathways and the IL-23/IL-17 Axis

Figure 2

This figure shows three novel intracellular signaling pathways involved in the pathogenesis of IBD. Pathway 1: TNF-α induces adhesion molecule expression in endothelial cells, as well as proinflammatory cytokine (IL-1β, IL-6) production by monocytes, through a sphingosine kinase (SK), sphingosine-1-phosphate (S1P), nuclear factor-kappa B (NF-κB)-dependent pathway. Pathway 2: upon stimulation of cells with proinflammatory cytokines (IFN-γ, TNF-α, and IL-1β), constitutive proteasome subunits are converted to the immunoproteasome subunits β1i (LMP2), β2i (LMP10, MECL-1), and β5i (LMP7) [38–40]. Functionally, immunoproteasome subunits play a role in NF-κB signaling. Pathway 3: dual activation of NF-κB and STAT3 pathways controls the expression of IL-17. As shown in this figure, crosstalk between these three pathways occurs, thereby promoting intestinal inflammation. Specific components of these pathways such as sphingosine kinase (SK), immunoproteasome subunits (LMP2, LMP7, and LMP10), and interactions between NF-κB/STAT3 represent possible pharmacological targets for IBD. In the figure: LMP is low molecular mass polypeptide (2, 5, or 10); JAK2 is Janus Kinase 2; PI3K is phosphoinositide-3 kinase; AKT1 is Alpha serine/threonine-protein kinase.