Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0043167 (pertussis)
 19,595 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Idiopathic pulmonary fibrosis (IPF)/usual interstitial pneumonia (UIP) is the severest form of idiopathic interstitial pneumonia for which therapeutic targets are needed. Surgical lung biopsy specimens from IPF/UIP patients exhibit focal expression of CC chemokine receptor (CCR) 7, but the identity of these CCR7-positive cells is unknown. The purpose of the present study was to examine the functional and signalling significance of CCR7 expression of primary fibroblasts grown from IPF/UIP and normal surgical lung biopsy specimens. Primary fibroblasts were cultured from surgical lung biopsy specimens from IPF/UIP and normal patients. Fibroblasts treated with or without CC chemokine ligand (CCL) 21 were analysed for functional, transcriptional and proteomic differences using immunocytochemical analysis, gene arrays, Taqman real-time PCR, and migration, proliferation and Western blot assays. CCR7 was expressed by IPF/UIP fibroblasts, but not normal fibroblasts. IPF/UIP fibroblasts, but not normal fibroblasts, showed significant migratory and proliferative responses when exposed to CCL21, which were inhibited by pertussis toxin or neutralising antibodies to CCR7. Exposure of IPF/UIP fibroblasts to CCL21 altered the phosphorylation status of mitogen-activated protein kinase kinase 1/2, extracellular signal-regulated kinase 1/2 and ribosomal S6 kinase (90 kDa) in these cells; this was abrogated by pertussis toxin or CCR7-specific small interfering RNA. Together, these data demonstrate that CC chemokine ligand 21 modulates the functional properties of idiopathic pulmonary fibrosis/usual interstitial pneumonia fibroblasts, but not normal fibroblasts.
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PMID:Idiopathic pulmonary fibrosis fibroblasts migrate and proliferate to CC chemokine ligand 21. 1733 65

The CC chemokine receptor (CCR)9 is expressed on the majority of small intestinal, but few colonic, T cells, whereas its ligand CCL25 is constitutively expressed by small intestinal epithelial cells. As such, CCR9/CCL25 have been proposed to play a central role in regulating small intestinal but not colonic immune responses and thus to organize regionalized immunity within the intestinal mucosa. Here, we demonstrate that CCL25 is expressed at reduced levels by epithelial cells in the distal compared with proximal small intestine, which correlated with less efficient CCR9-dependent effector CD8alphabeta+ T cell entry into the ileal epithelium. In vitro-generated alpha4beta7+ effector CD8alphabeta+ T cell entry into the lamina propria was less dependent on CCR9 than entry into the epithelium along the entire length of the small intestine and in particular in the ileum. CCR9-independent alpha4beta7+ effector CD8alphabeta+ T cell entry was pertussis toxin-sensitive, suggesting a role for additional Galpha(I)-linked G protein-coupled receptors. Finally, in vivo-primed effector CD8alphabeta+ T cells displayed regionalized differences in their entry to the small intestinal epithelium with enhanced CCR9-independent entry to the ileum. These results highlight a hitherto underappreciated compartmentalization of immune responses within the small intestine and have direct implications for targeting strategies aimed at regulating T cell localization to the small intestinal mucosa.
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PMID:Differential homing mechanisms regulate regionalized effector CD8alphabeta+ T cell accumulation within the small intestine. 1755 Oct 16

Human chemokine-like factor 1 (CKLF1) exhibits chemotactic effects on leukocytes. A previous study demonstrated that CKLF1 is a functional ligand for human CC chemokine receptor 4 (CCR4). In this study, N-terminal amino acid sequencing of secreted CKLF1 protein showed that it contains at least two peptides, C27 and C19. To examine whether C27 or C19 play a role via CCR4, C27 and C19 were chemically synthesized and analyzed by chemotaxis, calcium mobilization, and receptor internalization assays in CCR4-tranfected HEK293 cells or Hut78 cells. The chemotaxis assay showed that C27 could induce chemotaxis to CCR4-transfected HEK293 cells or Hut78 cells while C19 had weaker chemotactic activity, especially in Hut78 cells. C27- or C19-induced chemotaxis was abolished by pertussis toxin, suggesting the involvement of a Gi/o pathway. C27- or C19-induced chemotaxis was also inhibited by an antagonist of CCR4 that show good binding potency, excellent chemotaxis inhibitory activity and selectivity toward CCR4, suggesting that their chemotactic activity specifically involved CCR4. The chemotactic response of CCR4-tranfected HEK293 cells to C27 or C19 was markedly inhibited by preincubation with TARC/CCL17. TARC/CCL17 effectively desensitized the calcium mobilization induced by C27 or C19. Similarly, both of C27 or C19 also desensitized the calcium mobilization and chemotaxis of CCR4-tranfected HEK293 cells in response to TARC/CCL17, suggesting that they might interact with a common receptor. Both C27- and C19-induced clear internalization of CCR4-EGFP. These results confirm that the secreted peptides of CKLF1, C27 and C19, have functional activation via CCR4.
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PMID:Two C-terminal peptides of human CKLF1 interact with the chemokine receptor CCR4. 1806 42


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