Modulation of IL-4/IL-13 cytokine signaling in the context of allergic disease

Abstract

Aberrant activation of CD4 T_H2 cells and excessive production of T_H2 cytokines such as IL-4 and IL-13 have been implicated in the pathogenesis of allergic diseases. Generally, IL-4 and IL-13 utilize Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathways for induction of inflammatory gene expression and the effector functions associated with disease pathology in many allergic diseases. However, it is increasingly clear that JAK/STAT pathways activated by IL-4/IL-13 can themselves be modulated in the presence of other intracellular signaling programs, thereby changing the overall tone and/or magnitude of IL-4/IL-13 signaling. Apart from direct activation of the canonic JAK/STAT pathways, IL-4 and IL-13 also induce proinflammatory gene expression and effector functions through activation of additional signaling cascades. These alternative signaling cascades contribute to several specific aspects of IL-4/IL-13-associated cellular and molecular responses. A more complete understanding of IL-4/IL-13 signaling pathways, including the precise conditions under which noncanonic signaling pathways are activated, and the impact of these pathways on cellular- and host-level responses, will better allow us to design agents that target specific pathologic outcomes or tailor therapies for the treatment of uncommon disease endotypes.

Keywords: Allergic disease; IL-13; IL-4; cytokine signaling.

Figure 1:. Canonical and non-canonical IL-4 and IL-13 signaling pathways:

Canonical pathways (marked in dashed green box) activated in response to type I and type II IL-4R signaling involve JAK/STAT-mediated phosphorylation of STAT6. Activation of the type 1 IL-4R also leads to activation of IRS-2 and downstream activation of PI3K, Akt and mTOR. Non-canonical activation (marked in red dashed box) of SRC, ERK1/2 and p38 MAPK in response to IL-4, or ERK1/2 and PI3K in response to IL-13, have also been described to contribute important biological outcomes. As activation of PI3K/AKT/mTOR is directly attributable to γc/JAK3-driven phosphorylation of Y647 in IL-4Rα in the type 1 IL-4R complex, but IL-13Rα1/TYK2-driven phosphorylation of Y647 has not been described for the type II IL-4R, PI3K/AKT activation is considered canonical downstream of the type I IL-4R, but non-canonical downstream of the type II IL-4R complex. IL-13 can also signal through IL-13Rα2 (marked in dashed blue box) to activate/phosphorylate Akt/PKC and Ras/ERK1/2 pathway to induce TGFβ, Tenascin-c and other IL-13Rα2-associated genes.

Figure 2:. Negative and positive regulators of IL-4 and IL-13 signaling:

IL-13 and IL-4 signaling intermediates and receptors are marked in black and grey. Negative regulators (marked in red circles and red lines) of IL-4/13 signaling (SOCS proteins, protein tyrosine phosphatases) function by inhibiting JAK kinase activity, targeting activated signaling intermediates for proteolysis, and removing phosphate groups from activated signaling intermediates. Positive regulators (marked in green circles and green arrows) of IL-4/13 signaling pathway (PARP proteins, cAMP, S1P2 and IL-17A) facilitate efficient STAT6 DNA binding, protect STAT6 from proteolytic degradation, enhance STAT6 phosphorylation, enhance IL-4-induced gene expression through recruitment of C/EBPβ, and suppress SOCS3-mediated inhibition.