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. 2021 Jan 29;24(2):102112. doi: 10.1016/j.isci.2021.102112

Figure 4.

Figure 4

Model validation of essential pathway and marker signatures against untrained experimental data

Model simulations and corresponding macrophage experimental data (not included in calibration) are shown together (references are listed in the order of the data mentioned).

(A–C) IL-1β induces transient IκB degradation and activation of p38 and JNK (Hu et al., 2005).

(D–F) TNFα also induces IκB degradation and JNK activation (Pobezinskaya et al., 2008), and dose-dependent activation of p38 (Winston et al., 1997).

(G–I) IFNγ activates STAT1/IRF1 axis (Piccolo et al., 2017) and dose-dependently induces iNOS expression (Vila-Del Sol et al., 2007).

(J) Simultaneous treatment of IFNγ and IL-10 moderately upregulates VEGF secretion (Wu et al., 2010).

(K) IL-4 pretreatment decreases IFNγ-induced iNOS (Coccia et al., 2000).

(L) Inhibition of JNK decreases TNFα-induced upregulation of miR-155 (O'connell et al., 2007).

(M–P) IL-4 induces time course activation of STAT6 (Zhu et al., 2014) and AKT (Mccormick et al., 2016) and downstream expression of IRF4 and ARG1 (Binder et al., 2013).

(Q and R) (Q) Dose response of IL-4-mediated STAT6 activation (Heller et al., 2008); (R) dose response of IL-10-mediated STAT3 activation (Naiyer et al., 2013).

(S–U) Hypoxia stabilizes HIF1α/HIF2α and induces VEGF secretion (Fang et al., 2009); hypoxia also dose-dependently induces IKKβ expression (Cummins et al., 2006). (A–U) All values are normalized (y axes are relative expression levels) and are for proteins unless noted otherwise. For normalization of results (simulation and data in A–U): (A, D, J, and T) normalized to their respective t = 0 (Ctr) values; (K) normalized to the Ctr (IFNγ-treated) condition; (L) normalized to the Ctr (TNFα-treated) condition; (O and P) normalized to their respective values at 24 h of IL-4 treatment; (S) normalized to the respective values at 18 h of hypoxia; (H) normalized to the values at the last experimental time point; (I) normalized to the values at 25 ng/mL of IFNγ; all others normalized to their respective maximum values. S, simulation; D, experimental data; Hyp, hypoxia; Ctr, control/untreated condition (except in K and L as described above).