# Cytokines as therapeutic targets for cardio- and cerebrovascular diseases

**Authors:** Luca Liberale, Stefano Ministrini, Federico Carbone, Giovanni G. Camici, Fabrizio Montecucco

PMC · DOI: 10.1007/s00395-021-00863-x · 2021-03-26

## TL;DR

This paper explores how cytokines, which are key inflammatory mediators, can be targeted to treat heart and brain vascular diseases, with a focus on their role in atherosclerosis and potential therapeutic applications.

## Contribution

The paper provides a comprehensive review of cytokines' modulatory roles in cardio- and cerebrovascular diseases and evaluates their potential as therapeutic targets.

## Key findings

- Cytokines play a central role in the progression of atherothrombosis and inflammatory responses in cardiovascular and cerebrovascular diseases.
- Both stimulatory and inhibitory cytokines are being explored as disease markers and therapeutic targets.
- Chronic cytokine inhibition faces challenges due to harmful side effects, suggesting acute use in high-risk patients may be more viable.

## 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.

## Linked entities

- **Diseases:** atherosclerosis (MONDO:0005311), myocardial infarction (MONDO:0005068), stroke (MONDO:0005098)

## Full-text entities

- **Genes:** TYK2 (tyrosine kinase 2) [NCBI Gene 7297] {aka IMD35, JTK1}, IL6ST (interleukin 6 cytokine family signal transducer) [NCBI Gene 3572] {aka CD130, CDW130, GP130, HIES4, HIES4A, HIES4B}, TNFRSF1B (TNF receptor superfamily member 1B) [NCBI Gene 7133] {aka CD120b, TBPII, TNF-R-II, TNF-R75, TNFBR, TNFR1B}, THBS1 (thrombospondin 1) [NCBI Gene 7057] {aka THBS, THBS-1, TSP, TSP-1, TSP1}, Mapk8 (mitogen-activated protein kinase 8) [NCBI Gene 26419] {aka JNK, JNK1, Prkm8, SAPK1}, MAPK1 (mitogen-activated protein kinase 1) [NCBI Gene 5594] {aka ERK, ERK-2, ERK2, ERT1, MAPK2, NS13}, IL10 (interleukin 10) [NCBI Gene 3586] {aka CSIF, GVHDS, IL-10, IL10A, TGIF}, Cd4 (CD4 antigen) [NCBI Gene 12504] {aka L3T4, Ly-4}, IL36RN (interleukin 36 receptor antagonist) [NCBI Gene 26525] {aka FIL1, FIL1(DELTA), FIL1D, IL-36Ra, IL1F5, IL1HY1}, MMP3 (matrix metallopeptidase 3) [NCBI Gene 4314] {aka CHDS6, MMP-3, SL-1, STMY, STMY1, STR1}, JUN (Jun proto-oncogene, AP-1 transcription factor subunit) [NCBI Gene 3725] {aka AP-1, AP1, c-Jun, cJUN, p39}, Cdh5 (cadherin 5) [NCBI Gene 12562] {aka 7B4, Cd144, VE-Cad, VECD, VEcad, Vec}, Il17a (interleukin 17A) [NCBI Gene 16171] {aka Ctla-8, Ctla8, IL-17, IL-17A, Il17}, IL6R (interleukin 6 receptor) [NCBI Gene 3570] {aka CD126, HIES5, IL-1Ra, IL-6R, IL-6R-1, IL-6RA}, IL36B (interleukin 36 beta) [NCBI Gene 27177] {aka FIL1, FIL1-(ETA), FIL1H, FILI-(ETA), IL-1F8, IL-1H2}, Mmp2 (matrix metallopeptidase 2) [NCBI Gene 17390] {aka Clg4a, GelA, MMP-2}, BMX (BMX non-receptor tyrosine kinase) [NCBI Gene 660] {aka ETK, PSCTK2, PSCTK3}, Vcam1 (vascular cell adhesion molecule 1) [NCBI Gene 22329] {aka CD106, Vcam-1}, Il1 (interleukin 1 complex) [NCBI Gene 111343] {aka Il-1}, Tnfrsf1b (tumor necrosis factor receptor superfamily, member 1b) [NCBI Gene 21938] {aka CD120b, TNF-R-II, TNF-R2, TNF-R75, TNF-alphaR2, TNFBR}, CTLA4 (cytotoxic T-lymphocyte associated protein 4) [NCBI Gene 1493] {aka ALPS5, CD, CD152, CELIAC3, CTLA-4, GRD4}, MMP9 (matrix metallopeptidase 9) [NCBI Gene 4318] {aka CLG4B, GELB, MANDP2, MMP-9}, INS (insulin) [NCBI Gene 3630] {aka IDDM, IDDM1, IDDM2, ILPR, IRDN, MODY10}, Ifng (interferon gamma) [NCBI Gene 15978] {aka IFN-g, If2f, Ifg}, Mapk14 (mitogen-activated protein kinase 14) [NCBI Gene 26416] {aka CSBP2, Crk1, Csbp1, Mxi2, PRKM14, PRKM15}, STAT1 (signal transducer and activator of transcription 1) [NCBI Gene 6772] {aka CANDF7, IMD31A, IMD31B, IMD31C, ISGF-3, STAT91}, IL37 (interleukin 37) [NCBI Gene 27178] {aka FIL1, FIL1(ZETA), FIL1Z, IL-1F7, IL-1H, IL-1H4}, IL1A (interleukin 1 alpha) [NCBI Gene 3552] {aka IL-1 alpha, IL-1A, IL1, IL1-ALPHA, IL1F1}, Il10 (interleukin 10) [NCBI Gene 16153] {aka CSIF, If2a, Il-10}, ZHX2 (zinc fingers and homeoboxes 2) [NCBI Gene 22882] {aka AFR1, RAF}, Il1rn (interleukin 1 receptor antagonist) [NCBI Gene 16181] {aka F630041P17Rik, IL-1ra}, Icam1 (intercellular adhesion molecule 1) [NCBI Gene 15894] {aka CD54, Icam-1, Ly-47, MALA-2}, Stat3 (signal transducer and activator of transcription 3) [NCBI Gene 20848] {aka 1110034C02Rik, Aprf}, PIK3CG (phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit gamma) [NCBI Gene 5294] {aka IMD97, PI3CG, PI3K, PI3Kgamma, PIK3, p110gamma}, SERPINE1 (serpin family E member 1) [NCBI Gene 5054] {aka PAI, PAI-1, PAI1, PLANH1}, FGB (fibrinogen beta chain) [NCBI Gene 2244] {aka HEL-S-78p}, CASP1 (caspase 1) [NCBI Gene 834] {aka ICE, IL1BC, P45}, CXCL16 (C-X-C motif chemokine ligand 16) [NCBI Gene 58191] {aka CXCLG16, SR-PSOX, SRPSOX}, AKT1 (AKT serine/threonine kinase 1) [NCBI Gene 207] {aka AKT, PKB, PKB-ALPHA, PRKBA, RAC, RAC-ALPHA}, Il23r (interleukin 23 receptor) [NCBI Gene 209590] {aka IL-23R}, IL33 (interleukin 33) [NCBI Gene 90865] {aka C9orf26, DVS27, IL1F11, NF-HEV, NFEHEV}, CCL5 (C-C motif chemokine ligand 5) [NCBI Gene 6352] {aka D17S136E, RANTES, SCYA5, SIS-delta, SISd, TCP228}, CD40LG (CD40 ligand) [NCBI Gene 959] {aka CD154, CD40L, HIGM1, IGM, IMD3, T-BAM}, Selp (selectin, platelet) [NCBI Gene 20344] {aka CD62P, GMP-140, Grmp, LECAM3, PADGEM}, CXCR4 (C-X-C motif chemokine receptor 4) [NCBI Gene 7852] {aka CD184, D2S201E, FB22, HM89, HSY3RR, LCR1}, IL36A (interleukin 36 alpha) [NCBI Gene 27179] {aka FIL1, FIL1(EPSILON), FIL1E, IL-1F6, IL1(EPSILON), IL1F6}, IL1B (interleukin 1 beta) [NCBI Gene 3553] {aka IL-1, IL1-BETA, IL1F2, IL1beta}, TNFSF12 (TNF superfamily member 12) [NCBI Gene 8742] {aka APO3L, DR3LG, TNF12, TNLG4A, TWEAK}, TNFSF10 (TNF superfamily member 10) [NCBI Gene 8743] {aka APO2L, Apo-2L, CD253, TANCR, TL2, TNLG6A}, TRADD (TNFRSF1A associated via death domain) [NCBI Gene 8717] {aka Hs.89862}, AMH (anti-Mullerian hormone) [NCBI Gene 268] {aka MIF, MIS}, MYD88 (MYD88 innate immune signal transduction adaptor) [NCBI Gene 4615] {aka IMD68, MYD88D, WM1}, Jun (Jun proto-oncogene, AP-1 transcription factor subunit) [NCBI Gene 16476] {aka AP-1, Junc, c-jun}, TGFB1 (transforming growth factor beta 1) [NCBI Gene 7040] {aka CAEND1, CED, DPD1, IBDIMDE, LAP, TGF-beta1}, TRAF2 (TNF receptor associated factor 2) [NCBI Gene 7186] {aka MGC:45012, RNF117, TRAP, TRAP3}, Il23a (interleukin 23, alpha subunit p19) [NCBI Gene 83430] {aka IL-23, p19}, IFNG (interferon gamma) [NCBI Gene 3458] {aka IFG, IFI, IMD69}, NLRP3 (NLR family pyrin domain containing 3) [NCBI Gene 114548] {aka AGTAVPRL, AII, AVP, C1orf7, CIAS1, CLR1.1}, Il1a (interleukin 1 alpha) [NCBI Gene 16175] {aka Il-1a}, Ccl2 (C-C motif chemokine ligand 2) [NCBI Gene 20296] {aka HC11, JE, MCAF, MCP-1, MCP1, SMC-CF}
- **Diseases:** Ischemic strokeNo (MESH:D002545), cardiovascular inflammation (MESH:D007249), obesity (MESH:D009765), middle cerebral artery occlusion (MESH:D020244), Crohn disease (MESH:D003424), myocardial tissue (MESH:D002828), atherogenic (MESH:D050197), chronic inflammatory disease (MESH:D002908), ischemic myocardium (MESH:D017682), cerebral injury (MESH:D000070625), endothelial dysfunction (MESH:D014652), Thrombosis (MESH:D013927), Congestive Heart Failure (MESH:D006333), I/R injury (MESH:C580424), autoimmune diseases (MESH:D001327), NSTEMI (MESH:D000072658), BBB damage (MESH:C536830), neutropenia (MESH:D009503), ankylosing spondylitis (MESH:D013167), cardiac ischemia/reperfusion injury (MESH:D015427), infection (MESH:D007239), ischemic myocardial injury (MESH:D017202), hyperplasia (MESH:D006965), post-stroke deficits (MESH:D004834), bleeding (MESH:D006470), inflammatory arthritis (MESH:D001168), inflammatory bowel diseases (MESH:D015212), edema (MESH:D004487), unstable angina (MESH:D000789), ventricular dilatation, (MESH:C566255), ischemia (MESH:D007511), sepsis (MESH:D018805), neurotoxic (MESH:D020258), Cancer (MESH:D009369), ST Elevated Myocardial Infarction (MESH:D000072657), cardiac remodeling (MESH:D020257), coronary ligation (MESH:D003323), neurologic deficit (MESH:D009461), and cerebrovascular (MESH:D002561), RA (MESH:D001172), Ischemic Stroke (MESH:D002544), myocardial damage (MESH:D009202), Stroke (MESH:D020521), ischemic brain damage (MESH:D001925), Necrotic (MESH:D009336), Infarct size (MESH:D007238), necrotic core (MESH:D020512), fibrosis (MESH:D005355), cardiac and cerebral atherothrombotic complications (MESH:D006331), ischemic brain (MESH:D020520), tumor necrosis factors (MESH:C536657), auto-inflammatory (MESH:D018467), Psoriasis (MESH:D011565), plaque (MESH:D003773), atheroma (MESH:D058226), -MI (MESH:D009203), Ischemic strokei.v (MESH:C538155), systemic auto-inflammatory syndromes (MESH:D018746), cerebral damage (MESH:D002539), neuronal damage (MESH:D009410)
- **Chemicals:** Lipids (MESH:D008055), methotrexate (MESH:D008727), calcium (MESH:D002118), NO (MESH:D009614), cholesterol (MESH:D002784), cyclosporine (MESH:D016572), gevokizumab (MESH:C547697), HFNo (-), Infliximab (MESH:D000069285), serotonine (MESH:D012701), Tocilizumab (MESH:C502936), tofacitinib (MESH:C479163), prostaglandins (MESH:D011453), Canakinumab (MESH:C541220),  (MESH:D000893),  (MESH:D016207),  (MESH:D018836)
- **Species:** Oryctolagus cuniculus (domestic rabbit, species) [taxon 9986], Mus musculus (house mouse, species) [taxon 10090], Homo sapiens (human, species) [taxon 9606], Sus scrofa (pig, species) [taxon 9823], Rattus norvegicus (brown rat, species) [taxon 10116]

## Figures

1 figure with captions in the complete paper: https://tomesphere.com/paper/PMC7997823/full.md

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Source: https://tomesphere.com/paper/PMC7997823