Sustained Interleukin-1β Exposure Modulates Multiple Steps in Glucocorticoid Receptor Signaling, Promoting Split-Resistance to the Transactivation of Prominent Anti-Inflammatory Genes by Glucocorticoids

Figure 6

IL-1R1 signal transduction and negative regulation of GR-induced genes with known functions in inflammation and apoptosis: evidence of split GCR under sustained IL-1β conditions and proposed association with chemo- and GC-resistance phenotypes and EMT. (a) Signaling through the TAK1 and AKT parallel transduction nodes under normal IL-1R1 signaling conditions [44]. In the right node, TAK1 activates the three MAPK signaling cascades, including the JNK-AP1 pathway and the classical NFκB pathway. In the left node, AKT transiently promotes survival by inhibiting p53 and Bak/Bax-mediated apoptosis (thin black inhibition arrows) and also triggers a separate NF-κB/AP1 activation pathway (thin blue arrows) [47]. The schematic superimposes the most prominent effects mediated by the 6 selected GC-inducible genes (FKBP51, GILZ, DUSP1, TTP, IRF8, and IGFBP1, highlighted in green) in the regulation of IL-1R1 signaling under noninflammatory conditions. The level of wild-type FKBP51 contributes to low transient AKT activity, while IRF8 increases Bax expression and Bax/Bak pathway activities (bold arrows) which counteracts the AKT and IGFBP1 upstream survival regulation. GILZ, DUSP1, and TTP exert their regulatory functions as indicated by the bold inhibition arrows [2, 47–56]. (b) Under sustained IL-1β conditions, GC-driven transcription of FKBP51 is significantly reduced, which allows sustained AKT signaling (bold blue lines), which in turn has been associated with apoptosis- and chemo- and GC-resistance [52, 57]. IRF8 knockdown (in faded green) would reinforce the antiapoptotic AKT effects due to lower Bax expression and weak inhibition of other activities in the same pathway that lead to Bax-Bax pore formation (faded gray arrows) [55, 56]. The IGFBP1 overexpression would reinforce the antiapoptotic effects of AKT by further inhibiting activities that lead to Bak-Bak pore oligomerization [58] in the alternative pathway (faded and crossed-out). While GILZ and DUSP1 expression is unaffected in the IL-1β-induced split GCR model, sustained AKT activation might still reinforce the expression of the proinflammatory secretome via the noncanonical NF-κB/AP1 pathway (bold blue arrows) [47]. The latter might be potentiated by the reduction in TTP expression (2/3 less), a knockdown that has been also associated with EMT [54, 59].

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