The Selective CXCR2 Antagonist SB272844 Blocks Interleukin-8 and Growth-related Oncogene-α-mediated Inhibition of Spontaneous Neutrophil Apoptosis

Glynn, P.; Henney, E.; Hall, Ian P.

doi:10.1006/pupt.2001.0323

Cited by 50 publications

(40 citation statements)

References 20 publications

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“…We have shown recently that all the seven CXCR2 ligands are present in human colostrum and milk (50). An anti-apoptotic effect of growth-related oncoprotein-␣/CXCL1 has been observed in neutrophils (46). If the other chemokines in this subfamily indeed have a similar effect, this natural redundancy of CXCR2 ligands might be of teleologic advantage in intestinal development.…”

Section: Discussionmentioning

confidence: 94%

Interleukin-8/CXCL8 Forms an Autocrine Loop in Fetal Intestinal Mucosa

Maheshwari

Lacson

et al. 2004

Pediatr Res

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IL-8/CXC ligand (CXCL) 8 is ingested in high concentrationsby the human fetus/neonate with amniotic fluid and human milk, and is also produced constitutively by intestinal epithelial cells (IEC). We have shown that recombinant human IL-8/CXCL8 (rhIL-8/CXCL8) protects cultured IEC against tumor necrosis factor (TNF)-␣ and cycloheximide-induced cytotoxicity. In view of its constitutive production, we hypothesized that IL-8/CXCL8 might play an autocrine role in fetal enterocyte maintenance. In this study, we measured IL-8/CXCL8 mRNA concentrations in fetal intestine (11-22 wk gestation), sought the presence of the protein by immunohistochemistry in fetal stomach and intestine (9 -24 wk), measured IL-8/CXCL8 in neonatal gastric secretions, and studied constitutive and stimulated IL-8/CXCL8 expression in cultured IEC. We found that IL-8/CXCL8 is consistently transcribed and expressed in fetal intestinal tissue, in a developmentally regulated inverse relationship with gestational maturation. The cognate receptors for IL-8/CXCL8 are also expressed abundantly in the fetal intestine, and, therefore, we sought to determine whether the expressed IL-8/CXCL8 would complete an autocrine loop. Neutralization of IL-8/CXCL8 resulted in increased cell death in cultured IEC in the presence of TNF-␣.This effect is specifically mediated through the CXCR2 receptors. We speculate that IL-8/CXCL8 secretion during cytotoxic stress reflects a cellular self-defense mechanism. The human fetus and the neonate ingest biologically significant concentrations of IL-8/CXCL8 in amniotic fluid and human milk (1-5). We have shown recently that IL-8/CXCL8 remains intact through in vitro simulations of neonatal gastric digestion, and that it has a wide range of effects on cultured IEC (5, 6). Several investigators have also demonstrated both constitutive and regulated IL-8/CXCL8 expression in cultured IEC and intestinal organ culture, with evidence that such secretion is dynamically influenced by other cytokines and peptide growth factors (7)(8)(9)(10)(11).In this study, we studied IL-8/CXCL8 expression in the fetal/neonatal intestine by several modalities, and attempted to identify relationships, if any, with gestational age and IEC differentiation. We have previously shown that both the cognate receptors for IL-8/CXCL8, CXCR1 and CXCR2, are expressed in the fetal intestine as well as on several IEC lines. It is interesting that whereas TNF-␣ is a potent inducer of IL-8/CXCL8 secretion in IEC (7-11), its toxicity (in combination with cycloheximide) in these cells can be limited in vitro by rhIL-8/CXCL8 (5). We hypothesized that endogenously produced IL-8/CXCL8 plays an autocrine role in the intestinal mucosa with similar cytoprotective effects, and tested it in neutralization experiments. MATERIALS AND METHODS IL-8/CXCL8 Expression

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Section: Discussionmentioning

confidence: 94%

Interleukin-8/CXCL8 Forms an Autocrine Loop in Fetal Intestinal Mucosa

Maheshwari

Lacson

et al. 2004

Pediatr Res

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“…Because this protein is a receptor for interleukin-8, a key regulator of neutrophil migration, killing and survival (Glynn et al, 2002), this amino acid replacement potentially influences neutrophil function (a change in shape could modify the response to the ligand) and disease resistance. In addition, the protein and mRNA expression levels of interleukin-8 have been associated with bovine mastitis (Lee et al, 2006), which suggests participation of this chemokine in the process of developing the disease.…”

Section: Resultsmentioning

confidence: 99%

Single nucleotide polymorphisms in the CXCR1 gene and its association with clinical mastitis incidence in Polish Holstein-Friesian cows

et al. 2016

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“…The c.337A>G SNP changed the 113th amino acid from isoleucine to valine, whereas the c.365C>T mutation changed alanine to valine at position 122 within the putative 3rd intercellular loop of the receptor region for G protein coupling activation of CXCR1 (360 amino acids). Thus, these amino acid changes in CXCR1 potentially influence neutrophil function and disease resistance, because the product of the CXCR1 gene is a receptor for interleukin-8, a key regulator of neutrophil migration, killing, and survival (Glynn et al, 2002).…”

Section: Discussionmentioning

confidence: 99%