Associate editor: M.M. TeixeiraELR+ CXC chemokines and their receptors (CXC chemokine receptor 1 and CXC chemokine receptor 2) as new therapeutic targets
Introduction
Among chemotactic factors, chemokines are relatively small proteins (8–10 kDa) that direct the recruitment of leukocytes from the blood stream to the extravascular tissues (Mackay, 2001). Although this is a normal physiological response designed to fight infection, remove damaged cells and stimulate healing, an uncontrolled recruitment of leukocytes causes tissue damage, slows healing and in some cases may lead to host death. Therefore, inhibition of chemokine-induced biological activities may be an appropriate therapeutic strategy in a number of inflammatory diseases.
Chemokines have been classified into 4 subfamilies, based on the presence of cysteines at the amino terminal: CXC, CC, CX3C and C (Murphy et al., 2000, Gangur et al., 2002). Among chemokine subfamilies, CXC chemokines can be further subclassified into Glu-Leu-Arg (ELR)+ and ELR− CXC chemokines, based on the presence or absence of a tripeptide motif ELR at the NH2 terminus. Interleukin-8 (CXCL8), epithelial neutrophil activating protein (CXCL5), granulocyte chemotactic peptide-2 (CXCL6), neutrophilic activating protein (CXCL7), melanoma growth stimulatory activities (CXCL1, CXCL2 and CXCL3) belong to ELR+ CXC subfamily (Murphy et al., 2000). Characteristic of ELR+ chemokines is their ability to specifically recruit neutrophil polymorphonuclear leucocytes (PMN) into inflamed tissues. ELR+ chemokines-mediated PMN accumulation into sites of inflammation is a multistep process (rolling–adhesion–transmigration) and proceeds as a sequence of overlapping steps that enable cells to exit the blood stream and enter the peripheral tissues. This process occurs as a result of molecular changes on the surface of the endothelium in response to inflammatory stimuli. PMN may process numerous activating signals during rolling, and the transition from slow rolling to arrest occurs as a result of β2 integrin activation (Constantin et al., 2000). This activation allows high avidity interaction with their ligands on the endothelium, which can be triggered by immobilized ELR+ chemokines. Such arrested ELR+ chemokines are presented on the endothelial surface and are sufficient to induce PMN arrest from rolling (Rainger et al., 1997).
Two specific receptors for ELR+ chemokines, CXC chemokine receptor 1 (CXCR1) and CXC chemokine receptor 2 (CXCR2), have been identified on the cellular surface (Holmes et al., 1991, Murphy & Tiffany, 1991). Both receptors bind CXCL8 and CXCL6 with high and similar affinity whereas CXCR2 binds also with ELR+ CXC chemokines at high affinity (Lee et al., 1992, Petersen et al., 1994, Ahuja & Murphy, 1996). Although these 2 receptors have been characterized, their roles in mediating biological effects is not well defined. In fact, in vitro studies using anti-receptor monoclonal antibodies and cell lines expressing CXCR1 and CXCR2 have so far led to conflicting evidence as to the role of the 2 receptors in CXCL8-mediated cell chemotaxis (Loetscher et al., 1994, Chuntharapai & Kim, 1995, Quan et al., 1996, Ben-Baruch et al., 1997). However, increased evidences indicate that CXCR1 could have a dominant role in mediating CXCL8 chemotaxis of PMN that express both CXCL8 receptors (Hammond et al., 1995, Bertini et al., 2004, Di Cioccio et al., 2004).
On the other hand, CXCL8-stimulated keratinocyte proliferation and angiogenesis is supposed to be mainly mediated by CXCR2 activation (Addison et al., 2000).
This review focuses on the pathophysiological role played by ELR+ CXC chemokines on development of several pathologies including ulcerative colitis (UC), reperfusion injury (RI), bronchiolitis obliterans syndrome (BOS) and tumor progression.
Moreover, the most recent indications and therapeutic use of ELR+ CXC chemokine inhibitors, including neutralizing antibodies and small organic molecules, in preventing inflammatory disease progression is also discussed.
Section snippets
Ulcerative colitis
UC (Farrell & Peppercorn, 2002) is a chronic idiopathic inflammatory disorder of the intestine, which is characterized by rectal bleeding, severe diarrhea, abdominal pain, fever and weight loss. Histolologic examination of biopsies obtained from patients with active UC revealed the presence of a large number of leukocytes, mainly PMN, in the colonic mucosa. PMN infiltration was commonly paralleled by extensive mucosal and/or transmural injury including edema, loss of goblet cells, decreased
Antibodies
Two monoclonal antibodies against CXCL8 are in clinical trials.
Abgenix obtained ABX-IL-8, a fully human monoclonal antibody, by XenoMouse technology and filed the first Investigational New Drug (IND) in 1998. An extensive clinical program was designed in order to assess the therapeutic potential in metastatic melanoma, psoriasis, rheumatoid arthritis (RA) and COPD. The clinical development was discontinued in 2002 because the results of Phase 2 did not meet the primary efficacy endpoint for
Conclusions
Pharmacological research has confirmed the physiopathological key role of ELR+ CXC chemokines in several inflammatory pathologies. In fact, experimental and clinical results clearly indicate that ELR+ CXC chemokines and their receptors are directly involved in the development of UC, RI, BOS, COPD and tumor progression.
For this reason, the research of different pharmaceutical companies has been directed to the identification of selective antagonists of CXCL8 receptors.
Anti-chemokine strategies
References (123)
- et al.
The CXC chemokines growth-related oncogene (Gro)alpha, GRObeta, GROgamma, neutrophil-activating peptide-2, and epithelial cell-derived neutrophil-activating peptide-78 are potent agonists for the type B, but not the type A, human interleukin-8 receptor
J Biol Chem
(1996) - et al.
Hit-to-lead studies: the discovery of potent, orally bioavailable triazolethiol CXCR2 receptor antagonists
Bioorg Med Chem Lett
(2003) - et al.
Selective inhibition of interleukin-8-induced neutrophil chemotaxis by ketoprofen isomers
Biochem Pharmacol
(2001) - et al.
Inhibition of interleukin-8 blocks myocardial ischemia–reperfusion injury
J Thorac Cardiovasc Surg
(1998) - et al.
Characterization of the molecular interactions of interleukin-8 (CXCL8), growth related oncogen alpha (CXCL1) and a non-peptide antagonist (SB 225002) with the human CXCR2
Biochem Pharmacol
(2003) - et al.
Chemokines trigger immediate β2 integrin affinity and mobility changes: differential regulation and roles in lymphocyte arrest under flow
Immunity
(2000) - et al.
Anti-adhesion therapy
Adv Pharmacol
(1997) - et al.
Inhibition of the chemokine receptor CXCR2 prevents kidney graft function deterioration due to ischemia/reperfusion
Kidney Int
(2005) - et al.
Differential cytokine expression by human epithelial cell lines: regulated expression of interleukin-8
Gastroenterology
(1993) - et al.
Ulcerative colitis
Lancet
(2002)
Chemokines in health and disease
Vet Immunol Immunopathol
Neuroprotection with the CXCL8 inhibitor repertaxin in transient brain ischemia
Cytokine
Fully humanized neutralizing antibodies to interleukin-8 (ABX-IL8) inhibit angiogenesis, tumor growth, and metastasis of human melanoma
Am J Pathol
Neutrophil inhibitory factor treatment of focal cerebral ischemia in the rat
Brain Res
Characterization of two high affinity interleukin-8 receptors
J Biol Chem
Both interleukin-8 receptors independently mediate chemotaxis. Jurkat cells transfected with IL-8R1 or IL-8R2 migrate in response to IL-8, GRO alpha and NAP-2
FEBS Lett
Efficacy and safety of a monoclonal antibody recognizing interleukin-8 in COPD: a pilot study
Chest
Tumor–host interaction: analysis of cytokines, growth factors, and tumor-infiltrating lymphocytes in ovarian carcinomas
Hum Pathol
Neutralization of Gro alpha and macrophage inflammatory protein-2 attenuates renal ischemia/reperfusion injury
Am J Pathol
Distinct CXC chemokines mediate tumorigenicity of prostate cancer cells
Am J Pathol
Role of reactive metabolites of oxygen and nitrogen in inflammatory bowel disease
Free Radical Biology and Medicine
Antibodies against the N-terminus of IL-8 receptor A inhibit neutrophil chemotaxis
Biochem Biophys Res Commun
The CXC chemokine receptor 2, CXCR2, is the putative receptor for ELR+ CXC chemokine-induced angiogenic activity
J Immunol
Lung transplantation
N Engl J Med
Inhibition of interleukin-8 reduces tumorigenesis of human non-small cell lung cancer in SCID mice
J Clin Invest
Epithelial-neutrophil activating peptide (ENA-78) is an important angiogenic factor in non-small cell lung cancer
J Clin Invest
Cytokine/chemokine messenger-RNA expression profiles in ulcerative colitis and Crohn's disease
Virchows Arch
Chemokine expression in IBD. Mucosal chemokine expression is unselectively increased in both ulcerative colitis and Crohn's disease
J Pathol
The neutrophil as a mediator of myocardial ischemia–reperfusion injury: time to move on
Basic Res Cardiol
CXC chemokines in angiogenesis
J Leukoc Biol
Role of CXCR2/CXCR2 ligands in vascular remodelling during bronchiolitis obliterans syndrome
J Clin Invest
The different ability of IL-8 and neutrophil-activating peptide-2 to induce attenuation of chemotaxis is mediated by their divergent capabilities to phosphorylate CXCR2 (IL-8 receptor B)
J Immunol
Noncompetitive allosteric inhibitors of the inflammatory chemokine receptors CXCR1 and CXCR2: prevention of reperfusion injury
PNAS
Microvessel density in prostate cancer: prognostic and therapeutic utility
Semin Urol Oncol
Update on current and future pharmacologic therapy in COPD
Curr Med Chem-Anti-Inflammatory and Anti-Allergy Agents
Coexpression of interleukin-8 receptors in head and neck squamous cell calcinoma
Am J Surg
The selective CXCR2 receptor antagonist SB-656933 inhibits CXCL1-induced neutrophil CD11b expression in human whole blood
Eur Respir J
Ischemia-reperfusion of rat myocardium activates nuclear factor Kappa B and induces neutrophil infiltration via lipopolysaccharide-induced CXC chemochine
Circulation.
Up-regulation of tumor interleukin-8 expression by infiltrating macrophages: its correlation with tumor angiogenesis and patient survival in non-small cell lung cancer
Clin Cancer Res.
Regulation of the expression of IL-8 receptor A/B by IL-8: possible functions of each receptor
J Immunol
Cerebral protection in homozygous null ICAM-1 mice after middle cerebral artery occlusion. Role of neutrophil adhesion in the pathogenesis of stroke
J Clin Invest
Inflammation and cancer
Nature
Potential new drugs for therapy of chronic obstructive pulmonary disease
Expert Opin Investig Drugs
Upregulation of interleukin-8 by oxygen-deprived cells in glioblastoma suggests a role in leukocyte activation, chemotaxis, and angiogenesis
J Exp Med
Key role of proline-rich tyrosine kinase 2 in interleukin-8 (CXCL8/IL-8)-mediated human neutrophil chemotaxis
Immunology
Cited by (187)
Role of IL-6 and IL-8 biomarkers for optical and electrochemical based point-of-care detection of oral cancer
2022, Biosensors and Bioelectronics: XAnti-IL-8 antibody activates myeloid cells and potentiates the anti-tumor activity of anti-PD-1 antibody in the humanized pancreatic cancer murine model
2022, Cancer LettersCitation Excerpt :We also found that higher plasma IL-8 levels were correlated with poorer overall survival in PDAC patients who received vaccine therapy in combination with nivolumab (unpublished data). Thus, IL-8 and its receptors are valuable therapeutic targets in tumor therapies [32,33]. Monoclonal antibodies and small molecular inhibitors that block the IL-8-CXCR1/CXCR2 axis have been undergoing clinical development [34,35].
Design, synthesis and anti-tumor evaluation of 1,2,4-triazol-3-one derivatives and pyridazinone derivatives as novel CXCR2 antagonists
2021, European Journal of Medicinal ChemistryThe role of alcohol dehydrogenase 1C in regulating inflammatory responses in ulcerative colitis
2021, Biochemical PharmacologyChemokines in Cartilage Regeneration and Degradation: New Insights
2024, International Journal of Molecular Sciences