Functional interleuin-8 (IL-8) receptors (IL-8RA and IL-8RB:CXCR1 and CXCR2, respectively) have been described in human, monkey, dog, rabbit, and guinea pig. Although three IL-8R homologues have been found in rat, only one of these, rat CXCR2, appears to be functional based on responsiveness to ligands. Similarly, CXC chemokines induce biological responses through the murine homolog of CXCR2, but the identification of functional rodent CXCR1 homologues has remained elusive. We have identified and characterized the mouse CXCR1 homologue (mCXCR1). Murine CXCR1 shares 68 and 88% amino acid identity with its human and rat counterparts, respectively. Similar to the tissue distribution pattern of rat CXCR1, we found murine CXCR1 mRNA expression predominantly in lung, stomach, bone marrow, and leukocyte-rich tissues. In contrast to previous reports, we determined that mCXCR1 is a functional receptor. We show predominant engagement of this receptor by mouse GCP-2/CXCL6, human GCP-2, and IL-8/CXCL8 by binding, stimulation of GTP␥S exchange, and chemotaxis of mCXCR1-transfected cells. Furthermore, murine CXCR1 is not responsive to the human CXCR2 ligands ENA-78/CXCL5, NAP-2/CXCL7, GRO-␣, -, -␥/CXCL1-3, or rat CINC-1-3. In addition, we show concomitant elevation of mCXCR1 and its proposed major ligand, GCP-2, positively correlated with paw swelling in murine collagen-induced arthritis. This report represents the first description of a functional CXCR1-like receptor in rodents.
Inhibiting human immunodeficiency virus type 1 (HIV-1) infection by blocking the host cell coreceptors
Sch527123 [2-hydroxy-N,N-dimethyl-3-[[2-[[1(R)-(5-methyl-2-furanyl)propyl]amino]-3,4-dioxo-1-cyclobuten-1-yl]amino]benzamide] is a potent, selective antagonist of the human CXCR1 and CXCR2 receptors (Gonsiorek et al., 2007). Here we describe its pharmacologic properties at rodent CXCR2 and at the CXCR1 and CXCR2 receptors in the cynomolgus monkey, as well as its in vivo activity in models demonstrating prominent pulmonary neutrophilia, goblet cell hyperplasia, and mucus production. Sch527123 bound with high affinity to the CXCR2 receptors of mouse (K d ϭ 0.20 nM), rat (K d ϭ 0.20 nM), and cynomolgus monkey (K d ϭ 0.08 nM) and was a potent antagonist of CXCR2-mediated chemotaxis (IC 50 ϳ3-6 nM). In contrast, Sch527123 bound to cynomolgus CXCR1 with lesser affinity (K d ϭ 41 nM) and weakly inhibited cynomolgus CXCR1-mediated chemotaxis (IC 50 ϳ1000 nM). Oral treatment with Sch527123 blocked pulmonary neutrophilia (ED 50 ϭ 1.2 mg/kg) and goblet cell hyperplasia (32-38% inhibition at 1-3 mg/kg) in mice following the intranasal lipopolysaccharide (LPS) administration. In rats, Sch527123 suppressed the pulmonary neutrophilia (ED 50 ϭ 1.8 mg/kg) and increase in bronchoalveolar lavage (BAL) mucin content (ED 50 ϭ Ͻ0.1 mg/kg) induced by intratracheal (i.t.) LPS. Sch527123 also suppressed the pulmonary neutrophilia (ED 50 ϭ 1.3 mg/kg), goblet cell hyperplasia (ED 50 ϭ 0.7 mg/kg), and increase in BAL mucin content (ED 50 ϭ Ͻ1 mg/kg) in rats after i.t. administration of vanadium pentoxide. In cynomolgus monkeys, Sch527123 reduced the pulmonary neutrophilia induced by repeat bronchoscopy and lavage (ED 50 ϭ 0.3 mg/kg). Therefore, Sch527123 may offer benefit for the treatment of inflammatory lung disorders in which pulmonary neutrophilia and mucus hypersecretion are important components of the underlying disease pathology.Chronic obstructive pulmonary disease (COPD) is the fourth major cause of death in the United States and is characterized by irreversible airflow limitation due to chronic bronchitis or emphysema (Barnes and Stockley, 2005). The pathological hallmarks of COPD include peripheral airway inflammation dominated by neutrophils, the destruction of the lung parenchyma, submucosal gland hypertrophy, and goblet cell hyperplasia, as well as an increase in proinflammatory cytokines and chemokines (Barnes and Stockley, 2005). Current therapies for COPD are similar to those for asthma and include the use of -adrenoceptor agonists, theophylline, muscarinic antagonists, and corticosteroids (Barnes and Stockley, 2005). However, these treatments do not prevent the progressive decline in lung function and demonstrate clinical activity in only a subpopulation of COPD patients. There is a strong correlation between disease Article, publication date, and citation information can be found at
In neutrophils, growth-related protein-␣ (CXCL1) and interleukin-8 (CXCL8), are potent chemoattractants (Cytokine 14:27-36, 2001; Biochemistry 42: 2874 -2886, 2003) and can stimulate myeloperoxidase release via activation of the G protein-coupled receptors CXCR1 and CXCR2. The role of CXCR1 and CXCR2 in the pathogenesis of inflammatory responses has encouraged the development of small molecule antagonists for these receptors. The data presented herein describe the phar-, a novel antagonist of both CXCR1 and CXCR2. Sch527123 inhibited chemokine binding to (and activation of) these receptors in an insurmountable manner and, as such, is categorized as an allosteric antagonist. Sch527123 inhibited neutrophil chemotaxis and myeloperoxidase release in response to CXCL1 and CXCL8 but had no effect on the response of these cells to C5a or formyl-methionyl-leucyl-phenylalanine. The pharmacological specificity of Sch527123 was confirmed by testing in a diversity profile against a panel of enzymes, channels, and receptors. To measure compound affinity, we characterized [ 3 H]Sch527123 in both equilibrium and nonequilibrium binding analyses. Sch527123 binding to CXCR1 and CXCR2 was both saturable and reversible. Although Sch527123 bound to CXCR1 with good affinity (K d ϭ 3.9 Ϯ 0.3 nM), the compound is CXCR2-selective (K d ϭ 0.049 Ϯ 0.004 nM). Taken together, our data show that Sch527123 represents a novel, potent, and specific CXCR2 antagonist with potential therapeutic utility in a variety of inflammatory conditions.
The expression of the cannabinoid peripheral cannabinoid receptor (CB 2 ) receptor on peripheral immune cells suggests that compounds specific for CB 2 might be effective anti-inflammatory agents. In this report, we present the initial biological profiling of a novel triaryl bis-sulfone, Sch.336, which is selective for the human cannabinoid CB 2 receptor (hCB 2 ). Sch.336 is an inverse agonist at hCB 2 , as shown by its ability to decrease guanosine 5Ј-3-O-(thio)triphosphate (GTP␥S) binding to membranes containing hCB 2 , by the ability of GTP␥S to left-shift Sch.336 binding to hCB 2 in these membranes, and by the compound's ability to increase forskolin-stimulated cAMP levels in CHO cells expressing hCB 2 . In these systems, Sch.336 displays a greater potency than that reported for the CB 2 In vitro, Sch.336 impairs the migration of CB 2 -expressing recombinant cell lines to the cannabinoid agonist 2-arachidonylglycerol. In vivo, the compound impairs migration of cells to cannabinoid agonist HU210 [(6aR)-trans-3-(1,1-dimethylheptyl)-6a,7,10,10a-tetrahydro-1-hydroxy-6,6-dimethyl-6H-dibenzo [b,d] pyran-9-methanol]. Oral administration of the Sch.336 significantly inhibited leukocyte trafficking in several rodent in vivo models, induced either by specific chemokines or by antigen challenge. Finally, oral administration of Sch.336 blocked ovalbumin-induced lung eosinophilia in mice, a disease model for allergic asthma. We conclude that selective cannabinoid CB 2 inverse agonists may serve as novel immunomodulatory agents in the treatment of a broad range of acute and chronic inflammatory disorders in which leukocyte recruitment is a hallmark of disease pathology.The identification of a second cannabinoid receptor present primarily in peripheral immune tissues and cells (Munro et al., 1993) suggested an immunomodulatory role for endocannabinoids independent of the effects mediated by their interaction with the "brain" cannabinoid CB 1 receptor. Libraries of selective compounds now exist, based either on the structure of known ligands for the cannabinoid receptors or on results of random compound library screening (Huffman, 2000). With the help of CB 2 -specific compounds and by characterization of a CB 2 Ϫ/Ϫ mouse strain (Buckley et al., 2000), Article, publication date, and citation information can be found at
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