Cystic fibrosis gene expression is not correlated with rectifying Cl- channels.

Ward, Cristina L.; Krouse, Mauri E.; Gruenert, Dieter C.; Kopito, Ron R.; Wine, Jeffrey J.

doi:10.1073/pnas.88.12.5277

Cited by 59 publications

(21 citation statements)

References 38 publications

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“…B lymphoblast Cl ÿ channels derived from CF patients could not be activated by the cAMP-dependent pathway, suggesting that CFTR-dependent Cl ÿ channel defects are not limited in their expression to epithelial cells. Subsequently, CFTR transcription in lymphoblastoid cells was reported albeit at levels at least 1000-fold lower than highly expressing cells such as T84 [4,30,31]. While the presence of low copy lymphoblastoid CFTR mRNA has been interpreted by some to represent 'ectopic' or 'illegitimate' transcription of a tissue-specific gene [28,29,32], the functional relevance of CFTR transcription cannot be deduced on the basis of mRNA copy number.…”

Section: Discussionmentioning

confidence: 99%

Reduced IL-10 secretion by CD4+ T lymphocytes expressing mutant cystic fibrosis transmembrane conductance regulator (CFTR)

Moss¹,

Bocian²,

Hsu³

et al. 1996

Clinical and Experimental Immunology

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Expression of the CFTR protein is thought to be physiologically important only in exocrine epithelial cells. However, chronic respiratory inflammation and infection remain unexplained phenomena in disease pathogenesis. Non‐transformed, antigen‐responsive CD4+ T cells cloned from healthy controls and CF patients homozygous or heterozygous for the δF508 mutation transcribed CFTR mRNA and expressed immunoreactive cytoplasmic CFTR protein. T cell clones (TCC) from controls and CF patients displayed equivalent Ca2+‐mediated Cl− current; however, TCC from patients with CF but not controls displayed defective cAMP‐mediated Cl− current. Although CF‐derived TCC preserved mitogen and antigen proliferative responses and specificity to tetanus toxoid epitopes, they selectively secreted ≈ 45% less IL‐10 compared with control TCC after activation with concanavalin A (Con A) (624 ± 101 versus 1564 ± 401 pg/ml per 106 cells, respectively; P = 0.04) or anti‐CD3/phorbol ester (5148 ± 1634 versus 11 788 ± 2390 pg/ml; P = 0.05). This difference was independent of atopy. Secretion of interferon‐gamma, IL‐2, and IL‐4 was comparable in CF and control TCC after both forms of activation, while IL‐5 was reduced in CF TCC following anti‐CD3/phorbol myristate acetate (PMA) but not after Con A. We conclude that expression of mutant CFTR in human TCC is accompanied by ion channel dysfunction characteristic of the CF phenotype, and is accompanied by a reduction in IL‐10 secretion after polyclonal activation. It is possible that disruption of IL‐10‐mediated anti‐inflammatory homeostasis may contribute to early onset sustained inflammation in CF airways.

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Section: Discussionmentioning

confidence: 99%

Reduced IL-10 secretion by CD4+ T lymphocytes expressing mutant cystic fibrosis transmembrane conductance regulator (CFTR)

Moss¹,

Bocian²,

Hsu³

et al. 1996

Clinical and Experimental Immunology

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“…This channel had a single-channel conductance of ϳ50 pS and showed a characteristic outwardly rectifying current-voltage (I-V) relationship. On the basis of its single-channel properties, it was named the outwardly rectifying Cl Ϫ channel (ORCC) or intermediateconductance outwardly rectifying Cl Ϫ channel (ICOR) (222,259,643,656,657). Because of its abundance, ORCC was assumed to be the apical Cl Ϫ channel responsible for ion secretion.…”

Section: Intermediate-conductance Outwardly Rectifying CL ϫ Channelsmentioning

confidence: 99%

Electrolyte Transport in the Mammalian Colon: Mechanisms and Implications for Disease

Kunzelmann

Mall

2002

Physiological Reviews

580

571

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The colonic epithelium has both absorptive and secretory functions. The transport is characterized by a net absorption of NaCl, short-chain fatty acids (SCFA), and water, allowing extrusion of a feces with very little water and salt content. In addition, the epithelium does secret mucus, bicarbonate, and KCl. Polarized distribution of transport proteins in both luminal and basolateral membranes enables efficient salt transport in both directions, probably even within an individual cell. Meanwhile, most of the participating transport proteins have been identified, and their function has been studied in detail. Absorption of NaCl is a rather steady process that is controlled by steroid hormones regulating the expression of epithelial Na+ channels (ENaC), the Na+-K+-ATPase, and additional modulating factors such as the serum- and glucocorticoid-regulated kinase SGK. Acute regulation of absorption may occur by a Na+ feedback mechanism and the cystic fibrosis transmembrane conductance regulator (CFTR). Cl− secretion in the adult colon relies on luminal CFTR, which is a cAMP-regulated Cl− channel and a regulator of other transport proteins. As a consequence, mutations in CFTR result in both impaired Cl− secretion and enhanced Na+ absorption in the colon of cystic fibrosis (CF) patients. Ca2+- and cAMP-activated basolateral K+ channels support both secretion and absorption of electrolytes and work in concert with additional regulatory proteins, which determine their functional and pharmacological profile. Knowledge of the mechanisms of electrolyte transport in the colon enables the development of new strategies for the treatment of CF and secretory diarrhea. It will also lead to a better understanding of the pathophysiological events during inflammatory bowel disease and development of colonic carcinoma.

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“…Along with pivotal mutations localized in both NBDs, the large T-transfected tracheal CFT-1 and CFT-2 cells manifested the defect typical of C F which consists of impaired regulation of chloride conductance by cAMP [6,20]. Such a defect might be ascribed to the above reported mutations in CFTR, a protein whose mRNA transcripts are detected only after PCR amplification in tracheal epithelial cells [53,54]. Similarly we have detected a very low accumulation of the CFTR transcripts in the CFT-I and CFT-2 cells after PCR amplification (data not shown).…”

Section: Discussionmentioning

confidence: 99%

Oncogene‐mediated propagation of tracheal epithelial cells from two cystic fibrosis fetuses with different mutations. Characterization of CFT‐1 and CFT‐2 cells in culture

Lemnaouar

Chastre

Paul

et al. 1993

Eur J Clin Investigation

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Abstract. Primary tracheal epithelial cells obtained from two fetuses with cystic fibrosis (CF) were successfully transfected with a plasmid vector recombined with the large T oncogene of SV40. The resulting tracheal cells were propagated in culture for up to 25 passages and retained the mutations of the C F genes carried by the two fetuses, one heterozygous for the S549N and N1303K substitutions (CFT-I cells), and the other homozygous for the most common deletion AF508 (CFT-2 cells). The transfected cells: (a) expressed the SV40 large T oncogene, as determined by immunofluorescence and Northern blot analysis; (b) retained typical epithelial morphology, as assessed by the presence of microvilli, desmosomes, gap junctions, and cytokeratin expression; (c) were fully responsive to the CAMP-stimulating agents isproterenol, forskolin and vasoactive intestinal peptide for cAMP production and PKA activation; (d) do not produce any tumour in the athymic nude mice; (e) were diploid and tetraploid with a normal chromosomal complement at early passages, and (f) exhibited the abnormal regulation of chloride conductance characteristic of CF.These results indicate that CFT-I and CFT-2 cells constitute a suitable model for: (a) comparison of the maturation and function of the CFTR protein mutated in the two nucleotide-binding domains; (2) analysis of the biochemical defect in C F epithelial airway cells, (c) development of new therapeutic agents, and correction of the C F defect by gene replacement therapy in vitro.

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Cystic fibrosis gene expression is not correlated with rectifying Cl- channels.

Cited by 59 publications

References 38 publications

Reduced IL-10 secretion by CD4+ T lymphocytes expressing mutant cystic fibrosis transmembrane conductance regulator (CFTR)

Reduced IL-10 secretion by CD4+ T lymphocytes expressing mutant cystic fibrosis transmembrane conductance regulator (CFTR)

Electrolyte Transport in the Mammalian Colon: Mechanisms and Implications for Disease

Oncogene‐mediated propagation of tracheal epithelial cells from two cystic fibrosis fetuses with different mutations. Characterization of CFT‐1 and CFT‐2 cells in culture

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