Association of interleukin 8 receptor alpha polymorphisms with chronic obstructive pulmonary disease and asthma

Stemmler, Susanne; Arinir, Umut; Klein, Wolfram; Rohde, Gernot; Wirkus, N; Schultze‐Werninghaus, G.; Epplen, J. T.

doi:10.1055/s-2005-864322

Cited by 17 publications

(22 citation statements)

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“…As IL-8 secreted by a variety of inflammatory cells including monocytes has been implicated in a number of inflammatory/infectious diseases, such as rheumatoid arthritis [33], inflammatory bowel disease [34], psoriasis [35,36], palmoplantar pustulosis [37,38], asthma and chronic obstructive pulmonary disease [39], targeting P2Y 2 and/or P2Y 6 receptors may reveal as novel therapeutic approaches to fight these diseases. These data are also in agreement with a new concept proposing that extracellular nucleotides serve as endogenous danger-signaling molecules called alarmins that are (10 ng/mL) for 5 h in the presence or absence of semi-purified apyrase (2 U/mL) and/or P2 receptor antagonists (100 mM RB2, suramin, PPADS, or 10 mM MRS2578, respectively).…”

Section: Discussionmentioning

confidence: 99%

Concomitant activation of P2Y₂ and P2Y₆ receptors on monocytes is required for TLR1/2‐induced neutrophil migration by regulating IL‐8 secretion

et al. 2009

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Extracellular nucleotides regulate a variety of cellular responses involved in inflammation via the activation of P2 receptors. Here, we show that nucleotides regulate TLR2-induced neutrophil migration both in vivo and in vitro. The nucleotide scavenger apyrase inhibited neutrophil recruitment in murine air pouches injected with the TLR2 agonist Pam 3 CSK 4 . In agreement, the supernatants of either human primary monocytes or monocytic cells (THP-1 and U937) treated with Pam 3 CSK 4 recruited significantly fewer neutrophils when the former cells were treated in the presence of apyrase. As demonstrated with inhibitory Ab, these supernatants induced neutrophil migration due to IL-8 secretion. In addition, IL-8 secretion was markedly diminished by the non-selective P2 receptor antagonists reactive blue 2 and suramin, and by a selective P2Y 6 antagonist, MRS2578. Selective antagonists of P2Y 1 (MRS2500) and P2Y 11 (NF157) did not affect IL-8 release. The knockdown of either P2Y 2 or P2Y 6 with specific shRNA diminished IL-8 secretion from Pam 3 CSK 4 -treated THP-1 cells. Altogether, these results show that extracellular nucleotides, via P2Y 2 and P2Y 6 receptors, regulate neutrophil migration by controlling TLR2-induced IL-8 release from human monocytes. In line with our previous work on TLR4, this study further supports the importance of nucleotides in bacterial-induced neutrophil migration.Key words: Cell trafficking . Human monocytes . Inflammation . Neutrophils . Pam 3 CSK 4 IntroductionMonocytes play an important role in immune defences against invading bacteria and viruses via TLR activation [1]. TLR recognize highly conserved structural motifs expressed by microbes called PAMP. Monocytes express various TLR including TLR4 (that is activated by LPS, a cell wall component of Gramnegative bacteria), TLR2 (activated by peptidoglycan and lipopeptide, components of Gram-positive bacteria), TLR5 (activated by the bacterial flagellin) and TLR7/8 (activated by single-stranded viral RNA) [2][3][4][5]. In response to TLR activation by PAMP, monocytes release various cytokines and chemokines that orchestrate the innate immune responses [6][7][8]. For example, these cells secrete large amounts of the chemokine IL-8 that plays a major role in neutrophil recruitment at sites of infection [9].In addition to TLR, monocytes abundantly express P2 receptors that are activated by extracellular nucleotides. P2 receptors are divided into two subfamilies: the G-protein-coupled receptors (P2Y 1,2,4,6,[11][12][13][14] ) and the ligand-gated ion channels (P2X 1-7 ). The P2Y subtypes differ in their selectivity toward adenine (ATP, ADP) and uracil nucleotides (UTP, UDP) while all P2X receptors are activated by ATP [10,11]. Human primary monocytes and monocytic cell lines (THP-1 and U937) express the mRNA of various P2 receptors of which P2X 1,7 and P2Y 2,6,11 are common to all these cells [12,13]. There is growing evidence indicating that Results Extracellular nucleotides are involved in Pam 3 CSK 4 -induced neutrophil migration in vi...

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Section: Discussionmentioning

confidence: 99%

Concomitant activation of P2Y₂ and P2Y₆ receptors on monocytes is required for TLR1/2‐induced neutrophil migration by regulating IL‐8 secretion

et al. 2009

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“…We could not detect any polymorphisms in the promoter or the exon 1 region of either the patients or the controls. Sequence analysis of exon 2 (from the initiation methionine to the natural stop codon) revealed the presence of individuals heterozygous for two previously reported nonsynonymous polymorphisms (11,27): G827C, which leads to the change of serine to threonine at position 276 (S276T), and C1003T, which leads to the change of arginine to cysteine at position 335 (R335C). Among the patients, one individual carried the S276T polymorphism and another one carried the R335C polymorphism.…”

Section: Resultsmentioning

confidence: 99%

Expression of Interleukin-8 Receptors (CXCR1 and CXCR2) in Premenopausal Women with Recurrent Urinary Tract Infections

Smithson

Sarrias

Barceló

et al. 2005

Clin Vaccine Immunol

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The migration of neutrophils through infected tissues is mediated by the CXC chemokines and its receptors (CXCR1 and CXCR2). It has been proposed that a CXCR1 deficiency could confer susceptibility to acute pyelonephritis in children. The objective of the study is to assess the surface expression of CXCR1 and CXCR2 and the existence of polymorphisms in the CXCR1 gene in premenopausal women with recurrent urinary tract infections. The study included 20 premenopausal women with recurrent urinary infections, with normal urinary tracts, and without diseases potentially associated with relapsing urinary infections and 30 controls without previous urinary infections. The levels of CXCR1 and CXCR2 expression on neutrophils were measured and analyzed by flow cytometry by measuring the mean fluorescence intensity (MFI) channel. The promoter and coding regions of the CXCR1 gene were analyzed for the presence of polymorphisms by a sequence-based typing method. Patients with recurrent urinary tract infections exhibited median levels of CXCR1 expression, determined from MFI values, similar to those of the controls. The analysis of CXCR2 showed that patients with recurrent urinary infections had lower median levels of expression, determined from the MFI values, than the controls (P ‫؍‬ 0.002, Mann-Whitney U test). No polymorphisms were detected at the promoter or at the exon 1 region of the CXCR1 gene either in the patients or in the controls. Polymorphisms were detected at the exon 2 of CXCR1, but their frequencies did not differ between patients and controls. We have found a low level of CXCR2 expression in patients with recurrent urinary tract infections. These results suggest that a low level of CXCR2 expression may increase the susceptibilities of premenopausal women to urinary tract infections.Recurrent urinary tract infections (RUTIs) are frequent among healthy young women who generally have anatomically and physiologically normal urinary tracts (23). It has been estimated that each year in the United States about 6 million to 8 million young women have acute cystitis (20). Moreover, about 25% of these women who have had an initial infection will experience RUTIs, resulting in considerable morbidity and the associated health care costs (25). There is no satisfactory theory to explain the predisposition of some young healthy women with normal urinary tracts to RUTIs, but it seems to be the result of the combination of various factors inherited by the host and several behavioral conditions (5).In response to infection with uropathogenic Escherichia coli,

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“…IL8RA and IL8RB form a gene cluster in a region mapped to chromosome 2q35. In a recent study, one non-synonymous SNP in IL8RA showed significant association with chronic obstructive pulmonary disease (COPD) and asthma in a German cohort (Stemmler et al 2005). Moreover, the chromosome region in which IL8RA and IL8RB lie revealed the highest linkage to spirometric phenotypes for earlyonset COPD in genome-wide screening (Palmer et al 2003).…”

Section: Introductionmentioning

confidence: 99%

Polymorphisms in interleukin 8 and its receptors (IL8, IL8RA and IL8RB) and association of common IL8 receptor variants with peripheral blood eosinophil counts

et al. 2006

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Airway inflammation is a major factor in the pathogenesis of asthma. Interleukin 8 (IL8) is a potent proinflammatory cytokine that interacts with its receptors, IL8RA and IL8RB. We investigated the genetic polymorphisms in IL8, IL8RA, and IL8RB for any association with risk of asthma and peripheral blood eosinophil counts in a Korean population. By carrying out direct sequencing in 24 individuals, we identified 20 sequence variants within exons and their flanking regions, including the 1.5 kb promoter regions of IL8, IL8RA, and IL8RB. Among them, seven common single-nucleotide polymorphisms (SNPs) were selected for genotyping in our asthma cohort (n = 1,439). Two common haplotypes in IL8 and three in IL8RA and IL8RB (defined as one block) were identified. Although none of the polymorphisms showed a significant association with risk of asthma, IL8RA-B ht2 showed a significant association with the peripheral blood eosinophil counts (%) among asthma patients, e.g., lower eosinophil levels among individuals with the homozygous IL8RA-B ht2 (3.55 ± 3.39%) than among other asthmatic patients (5.52 ± 5.55%; P corr = 0.018). Our findings suggest that polymorphisms and haplotypes in IL8RA and IL8RB might be among the genetic factors underlying production of peripheral blood eosinophil.

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Association of interleukin 8 receptor alpha polymorphisms with chronic obstructive pulmonary disease and asthma

Cited by 17 publications

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Concomitant activation of P2Y₂ and P2Y₆ receptors on monocytes is required for TLR1/2‐induced neutrophil migration by regulating IL‐8 secretion

Concomitant activation of P2Y₂ and P2Y₆ receptors on monocytes is required for TLR1/2‐induced neutrophil migration by regulating IL‐8 secretion

Expression of Interleukin-8 Receptors (CXCR1 and CXCR2) in Premenopausal Women with Recurrent Urinary Tract Infections

Polymorphisms in interleukin 8 and its receptors (IL8, IL8RA and IL8RB) and association of common IL8 receptor variants with peripheral blood eosinophil counts

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Association of interleukin 8 receptor alpha polymorphisms with chronic obstructive pulmonary disease and asthma

Cited by 17 publications

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Concomitant activation of P2Y2 and P2Y6 receptors on monocytes is required for TLR1/2‐induced neutrophil migration by regulating IL‐8 secretion

Concomitant activation of P2Y2 and P2Y6 receptors on monocytes is required for TLR1/2‐induced neutrophil migration by regulating IL‐8 secretion

Expression of Interleukin-8 Receptors (CXCR1 and CXCR2) in Premenopausal Women with Recurrent Urinary Tract Infections

Polymorphisms in interleukin 8 and its receptors (IL8, IL8RA and IL8RB) and association of common IL8 receptor variants with peripheral blood eosinophil counts

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Concomitant activation of P2Y₂ and P2Y₆ receptors on monocytes is required for TLR1/2‐induced neutrophil migration by regulating IL‐8 secretion

Concomitant activation of P2Y₂ and P2Y₆ receptors on monocytes is required for TLR1/2‐induced neutrophil migration by regulating IL‐8 secretion