Theoretical Studies on the Engagement of Interleukin 18 in the Immuno-Inflammatory Processes Underlying Atherosclerosis

Abstract

Interleukin 18 (IL-18) is one of the pro-inflammatory cytokines expressed by macrophages, suggesting that it plays important physiological and immunological functions, among the others: stimulation of natural killers (NKs) and T cells to interferon gamma (IFN- γ ) synthesis. IL-18 was originally identified as interferon gamma inducing factor and now it is recognized as multifunctional cytokine, which has a role in regulation of innate and adaptive immune responses. Therefore, in order to investigate IL-18 contribution to the immuno-inflammatory processes underlying atherosclerosis, a systems approach has been used in our studies. For this purpose, a model of the studied phenomenon, including selected pathways, based on the Petri-net theory, has been created and then analyzed. Two pathways of IL-18 synthesis have been distinguished: caspase 1-dependent pathway and caspase 1-independent pathway. The analysis based on t-invariants allowed for determining interesting dependencies between IL-18 and different types of macrophages: M1 are involved in positive regulation of IL-18, while M2 are involved in negative regulation of IL-18. Moreover, the obtained results showed that IL-18 is produced more often via caspase 1-independent pathway than caspase 1-dependent pathway. Furthermore, we found that this last pathway may be associated with caspase 8 action.

Keywords: Petri nets; atherosclerosis; interleukin 18; macrophages; modeling; t-invariants.

Figure 1

The diagram presents a count of t-invariants corresponding to subprocesses in which IL-18 produced by different pathways is engaged.

Figure 2

The diagram presents a count of t-invariants corresponding to subprocesses in which caspase 8 is engaged.

Figure 3

The diagram presents a count of t-invariants corresponding to subprocesses in which different types of macrophages are engaged.

Figure 4

The diagram of the phenomena underlying the atherosclerotic lesions formation. The elements which are marked with the same colour and name correspond to the same particle (logic place). Element “51” corresponds to p50/p65 proteasome inhibitors induce inhibitory $\kappa$B (I$\kappa$B) phosphorylated complex within macrophages. Element “52” corresponds to p50/p65 dimer nuclear factor kappa-light-chain-enhancer of activated B cells (NF-$\kappa$B) early phase in activated endothelial cell (EC) in atherosclerosis. Element “53” corresponds to p50/p65 dimer nuclear factor kappa-light-chain-enhancer of activated B cells (NF-$\kappa$B)) early phase in activated smooth muscle cells (SMC). Element “61” corresponds to p50/p65 proteasome inhibitors induce inhibitory $\kappa$B (I$\kappa$B) phosphorylated complex in activated SMC. Element “p50/p65” corresponds to p50/p60 translocation to the nucleus in macrophages M1 and SMC and endothelial cells (EC).

Figure 5

The proposed model has been divided into parts corresponding to the biological phenomena: (a) Janus kinases and signal transducer and activator of transcription (JAK-STAT) pathway stimulated by interferon gamma (IFN$\gamma$); (b) innate immune responses; (c) p50/p65 translocation to the nucleus in macrophages M1, smooth muscle cell (SMC) and endothelial cell (EC); (d) gram-negative bacterial infections; (e) activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-$\kappa$B)—the canonical pathway via I$\kappa$B$\alpha$ phosphorylation by kinase complex (IKK) (MyD88-dependent signaling pathway); (f) activation of caspase 1 (by tumor necrosis factor (TNF) and also by binding with STAT binding element (SBE) sequences of interferon regulatory factor I (IRF1); (g) IL-18 synthesis (caspase 1-dependent pathway); (h) IL-18-IL-18R complex formation; (i) negative regulation of IL-18 (by inhibition of caspase 1) caused by nitric oxide (NO); (j) NO synthesis; (k) cardiovascular disease influenced by NO-dependent pathway; (l) TNF receptor-associated factor 2 (TRAF2) and receptor-interacting serine/threonine-protein (kinase 1 (RIP1) ubiquitination; (m) macrophages polarization; (n) lipid peroxidation (oxLDL); (o) IL-18 synthesis (caspase 1-independent pathway) and neighboring endothelial cells stimulation; (p) regulation of TNFR1 signaling; (r) the role of IL-1, IL-23, IL-6, high level of IL-10 and IL-12 (released by classically activated macrophages M1); (s) atherosclerosis progression; (t) attracting of monocytes (classically activated macrophages M1); (u) formation of apoptosome and activation of effector caspases 3, 6, 7; (w) high level of active caspase 8; (x) inhibition of caspase 8 and inhibition of apoptosis (by a high level of cFLIPs); (y) STAT6 upregulation promotes M2 macrophage polarization to suppress atherosclerosis.

Figure 6

The scheme of work: creating models, methods of analysis, and obtaining results.

Figure 7

The influence of different types of macrophages on IL-18. The results suggest that caspase 1-independent pathway may be associated with caspase 8 action.