Cytokines as therapeutic targets for cardio- and cerebrovascular diseases

Abstract

Despite major advances in prevention and treatment, cardiac and cerebral atherothrombotic complications still account for substantial morbidity and mortality worldwide. In this context, inflammation is involved in the chronic process leading atherosclerotic plaque formation and its complications, as well as in the maladaptive response to acute ischemic events. For this reason, modulation of inflammation is nowadays seen as a promising therapeutic strategy to counteract the burden of cardio- and cerebrovascular disease. Being produced and recognized by both inflammatory and vascular cells, the complex network of cytokines holds key functions in the crosstalk of these two systems and orchestrates the progression of atherothrombosis. By binding to membrane receptors, these soluble mediators trigger specific intracellular signaling pathways eventually leading to the activation of transcription factors and a deep modulation of cell function. Both stimulatory and inhibitory cytokines have been described and progressively reported as markers of disease or interesting therapeutic targets in the cardiovascular field. Nevertheless, cytokine inhibition is burdened by harmful side effects that will most likely prevent its chronic use in favor of acute administrations in well-selected subjects at high risk. Here, we summarize the current state of knowledge regarding the modulatory role of cytokines on atherosclerosis, myocardial infarction, and stroke. Then, we discuss evidence from clinical trials specifically targeting cytokines and the potential implication of these advances into daily clinical practice.

Keywords: Cardiovascular disease; Cerebrovascular disease; Cytokines; IL-1; IL-6; Interleukins.

Fig. 1

Signaling pathways of the main cytokines involved in cardiovascular diseases. Four main cytokines have been extensively investigated in cardiovascular diseases: tumor necrosis factor α (TNF-α), interleukin 1 (IL-1), IL-6, and IL-10. The intracellular signaling pathways of TNF-α and IL-1 (panel A) converge on two main transcription factors: nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and activator protein 1 (AP-1). Their overall effect is pro-inflammatory. The receptor of TNF-α has two isoforms (TNFR1 and -2). The transduction of signal of TNFR1 is driven by the TNFR1-associated death domain protein (TRADD), which activates the mitogen-activated kinases (MAPKs), namely the extracellular-signal-regulated kinases 1 and 2 (ERK 1/2), the cJun-terminal kinase (JNK), and the p38. In turn, the MAPKs activate c-Jun and phosphorylate the inhibitor of NF-κB (IκB), determining the activation of NF-κB and AP-1. TNFR1 can also activate the protein-kinase C (PKC), that is a Ca²⁺-calmodulin-dependent kinase, that promotes the rearrangement of the cytoskeleton and blunts the contractility of sarcomeres in cardiomyocytes. The transduction of signal of TNFR2 is driven by the TNFR-associated factor 2 (TRAF2) and the endothelial/epithelial tyrosine kinase (ETK). TRAF2 activates the IκB kinase α (IKKα), which phosphorylates IκB and activates NF-κB through the non-canonical pathway, having a final immune-modulatory effect, whereas the canonical pathway leads to apoptosis, increase of oxidative stress, and pro-inflammatory signaling. ETK activates the adaptor protein Akt through the phosphoinositol-3-kinase (PI3K), and eventually activates NF-κB through the non-canonical pathway. IL-1 has two main isoforms, IL-1α and IL-1β, which interact with the same receptor. The intracellular signaling pathway of IL-1 is driven by the myeloid differentiation factor 88 (MyD88), which activates multiple kinases, named interleukin-1-associated kinases (IRAKs), which in turn activate multiple IKKs and the activation of NF-κB through the canonical pathway. The intracellular signaling pathways of IL-6 and IL-10 (panel B) converge on two main transcription factors: NF-κB and the family of signal transducers and activators of transcription (STAT). The overall effect of IL-6 is pro-inflammatory, whereas IL-10 is the main anti-inflammatory cytokine in humans. IL-6 receptor α (IL-6Rα) can be bound to the cell membrane or free in a soluble form (sIL-6Rα). The transduction of signal is initiated by the binding of the receptor with the glycoprotein 130 (gp130), and it may follow two main pathways: the Janus kinase (JAK) pathway and the Ras pathway, through the adaptor proteins Shc. and Son-of-sevenless (SOS). Ras activates the MAPKs’ cascade (namely Raf, MEK 1/2, and ERK 1/2), which activates NF-κB through the canonical pathway. Ras can also activate the PI3K/Akt cascade and NF-κB through the non-canonical pathway. JAK phosphorylates Akt, which in turn promotes migration of STAT inside the nucleus, where it can exert its transcriptional function. The activation of STAT has an overall anti-inflammatory effect, and it inhibits the JAK signaling through a negative feedback mechanism, mediated by the suppressor of cytokine signaling (SOCS). The signaling of IL-10 can be mediated by JAK, through the pathway described above, or through the tyrosine kinase 2 (TYK2). Both pathways converge on STAT