Leukocyte trafficking to inflammatory sites is a gradual process, which is dominated in its early phases by chemokine-and cytokine-mediated neutrophil recruitment. The chemokine regulated on activation normal T cell expressed and secreted (RANTES) has been shown to be highly expressed in the joints of patient with rheumatoid arthritis and to promote leukocyte trafficking into the synovial tissue. In this study, we investigated the effect of RANTES in a murine model of peritoneal chemotaxis, and we found that RANTES dose-dependently induces neutrophil recruitment. Then, through morphological and histological analyses, we observed that activated neutrophils represent the major infiltrating population in response to RANTES chemotactic stimulus. Furthermore, we demonstrated that oral administration of either nonisoform-specific phosphoinositide 3-kinase (PI3K) inhibitor LY294002 (morpholin-4-yl-8-phenylchromen-4-one) or selective PI3K␥ inhibitor AS041164 (5-benzo[1,3]dioxol-5-ylmethylene-thiazolidine-2,4-dione) blocks RANTES-induced chemotaxis and reduces the level of AKT phosphorylation. Because the two compounds showed a similar pharmacokinetic profile in terms of bioavailability and half-life after oral route administration, the selective inhibition of the PI3K␥-isoform pathway through AS041164 was three times more potent in reducing neutrophil recruitment. Finally, to confirm the blockade of neutrophil infiltration that occurs in the early phase of the inflammatory response, AS041164 was also tested in a model of carrageenan-induced paw edema in rats. Therefore, the PI3K␥ pathway plays an important role in controlling neutrophil chemotaxis during early steps of inflammation.During inflammation, neutrophils are rapidly recruited at sites of acute infection and dominate the initial influx of leukocytes (Issekutz and Movat, 1980). Later, during the progression of inflammation, monocytes and macrophages replace neutrophils, suggesting a bimodal recruitment pattern involving a switch from neutrophils to monocytes (Doherty et al., 1988;Henderson et al., 2003). The first step in approaching a site of insult requires neutrophils to transmigrate across endothelial barriers, a process that depends on chemokines (Yoshie et al., 2001). In response to a chemotactic gradient, CXC and CC chemokines activate leukocytes by binding to seven transmembrane receptors coupled to G proteins (Proudfoot, 2002) linked to heterotrimeric G protein complexes (Proudfoot, 2002). Upon stimulation, the G protein complex dissociates and subsequently recruits various signaling components, such as nucleotide exchange factors, phospholipid lipases, and lipid kinase phosphoinositide-3ЈOH-kinase isoforms, such as phosphoinositide 3-kinase (PI3K) (Akasaki et al., 1999). Neutrophils have been shown to express different chemokine receptors, including CXCR2 and CCR1 (Lee et al., 1995;Zhang et al., 1999). Furthermore, the blockade of the chemokine receptor CXCR2 or its ligands IL-8 and macrophage inflammatory protein (MIP)-2, or alternatively of t...
A chimeric recombinant human gonadotropin, termed C3, demonstrates both follitropic and lutropic bioactivities. The alpha-subunit construct for C3 is comprised of the recombinant wild-type human glycoprotein hormone alpha-subunit. The beta-subunit DNA construct for C3 encodes residues 1-145 from human chorionic gonadotropin (hCG)-beta with the exceptions that FSH beta amino acid 88 (D) is substituted for hCG beta amino acid 94 (R) and FSH beta amino acids 95-108 (TVRGLGPSYCSFGE) are substituted for hCG beta amino acids 101-114 (GGPKDHPLTCDDPR). C3 is a potent FSH and LH agonist able to bind and to signal through FSH and LH receptors in vitro. In in vivo bioassays optimized to quantify each type of activity, C3 was found to have lutropin and follitropin potencies at levels similar to those of recombinant human LH and recombinant human FSH, respectively. In immature rats, C3 was sufficient to support the maturation of normal ovarian follicles. Moreover, a significant portion of follicles matured by C3 ruptured in response to an ovulatory hCG stimulus and gave rise to morphologically normal oocytes. Furthermore, a low dose of C3 promoted weight gain in the rodent uterus, suggesting it also supported preparation for implantation without histological evidence of excessive luteinization of the ovary. In summary, the biological properties of C3 indicate that its chimeric nature has resulted in a fully functional, dual-acting human gonadotropin.
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