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PubMed1980

Temperature-sensitive glutamate dehydrogenase mutants of Salmonella typhimurium.

Mutants of Salmonella typhimurium defective in glutamate dehydrogenase activity were isolated in parent strains lacking glutamate synthase activity by localizcd mutagenesis or by a general mutagenesis combined with a cycloserine enrichment for glutamate auxotrophs. Two mutants with temperature-sensitive phenotypes had glutamate dehydrogenase activities that were more thermolabile than that of an isogenic control strain. Eight other mutants had less than 10% of the wild-type glutamate dehydrogenase activity. All the mutations were cotransducible with a Tn10 element (zed-2:Tn10) located at approximately 23 U on the S. typhimurium linkage map. These data strongly indicate that this region contains the structural gene (gdhA) for glutamate dehydrogenase.

Chromosome Mapping↗

PubMed1996

Topoisomerase I involvement in illegitimate recombination in Saccharomyces cerevisiae.

Chromosome aberrations may cause cancer and many heritable diseases. Topoisomerase I has been suspected of causing chromosome aberrations by mediating illegitimate recombination. The effects of deletion and of overexpression of the topoisomerase I gene on illegitimate recombination in the yeast Saccharomyces cerevisiae have been studied. Yeast transformations were carried out with DNA fragments that did not have any homology to the genomic DNA. The frequency of illegitimate integration was 6- to 12-fold increased in a strain overexpressing topoisomerase I compared with that in isogenic control strains. Hot spot sequences [(G/C)(A/T)T] for illegitimate integration target sites accounted for the majority of the additional events after overexpression of topoisomerase I. These hot spot sequences correspond to sequences previously identified in vitro as topoisomerase I preferred cleavage sequences in other organisms. Furthermore, such hot spot sequences were found in 44% of the integration events present in the TOP1 wild-type strain and at a significantly lower frequency in the top1delta strain. Our results provide in vivo evidence that a general eukaryotic topoisomerase I enzyme nicks DNA and ligates nonhomologous ends, leading to illegitimate recombination.

Base Sequence↗

PubMed2024

Reversion from basal histone H4 hypoacetylation at the replication fork increases DNA damage in FANCA deficient cells.

The FA/BRCA pathway safeguards DNA replication by repairing interstrand crosslinks (ICL) and maintaining replication fork stability. Chromatin structure, which is in part regulated by histones posttranslational modifications (PTMs), has a role in maintaining genomic integrity through stabilization of the DNA replication fork and promotion of DNA repair. An appropriate balance of PTMs, especially acetylation of histones H4 in nascent chromatin, is required to preserve a stable DNA replication fork. To evaluate the acetylation status of histone H4 at the replication fork of FANCA deficient cells, we compared histone acetylation status at the DNA replication fork of isogenic FANCA deficient and FANCA proficient cell lines by using accelerated native immunoprecipitation of nascent DNA (aniPOND) and in situ protein interactions in the replication fork (SIRF) assays. We found basal hypoacetylation of multiple residues of histone H4 in FA replication forks, together with increased levels of Histone Deacetylase 1 (HDAC1). Interestingly, high-dose short-term treatment with mitomycin C (MMC) had no effect over H4 acetylation abundance at the replication fork. However, chemical inhibition of histone deacetylases (HDAC) with Suberoylanilide hydroxamic acid (SAHA) induced acetylation of the FANCA deficient DNA replication forks to levels comparable to their isogenic control counterparts. This forced permanence of acetylation impacted FA cells homeostasis by inducing DNA damage and promoting G2 cell cycle arrest. Altogether, this caused reduced RAD51 foci formation and increased markers of replication stress, including phospho-RPA-S33. Hypoacetylation of the FANCA deficient replication fork, is part of the cellular phenotype, the perturbation of this feature by agents that prevent deacetylation, such as SAHA, have a deleterious effect over the delicate equilibrium they have reached to perdure despite a defective FA/BRCA pathway.

Histones↗

PubMed2002

Evidence for a modulation of neutral trehalase activity by Ca2+ and cAMP signaling pathways in Saccharomyces cerevisiae.

Saccharomyces cerevisiae neutral trehalase (encoded by NTH1) is regulated by cAMP-dependent protein kinase (PKA) and by an endogenous modulator protein. A yeast strain with knockouts of CMK1 and CMK2 genes (cmk1cmk2) and its isogenic control (CMK1CMK2) were used to investigate the role of CaM kinase II in the in vitro activation of neutral trehalase during growth on glucose. In the exponential growth phase, cmk1cmk2 cells exhibited basal trehalase activity and an activation ratio by PKA very similar to that found in CMK1CMK2 cells. At diauxie, even though both cells presented comparable basal trehalase activities, cmk1cmk2 cells showed reduced activation by PKA and lower total trehalase activity when compared to CMK1CMK2 cells. To determine if CaM kinase II regulates NTH1 expression or is involved in post-translational modulation of neutral trehalase activity, NTH1 promoter activity was evaluated using an NTH1-lacZ reporter gene. Similar beta-galactosidase activities were found for CMK1CMK2 and cmk1cmk2 cells, ruling out the role of CaM kinase II in NTH1 expression. Thus, CaM kinase II should act in concert with PKA on the activation of the cryptic form of neutral trehalase. A model for trehalase regulation by CaM kinase II is proposed whereby the target protein for Ca2+/CaM-dependent kinase II phosphorylation is not the neutral trehalase itself. The possible identity of this target protein with the recently identified trehalase-associated protein YLR270Wp is discussed.

Calcium-Calmodulin-Dependent Protein Kinase Type 2↗

PubMed2003

Effect of feeding glyphosate-tolerant (roundup-ready events GA21 or nk603) corn compared with reference hybrids on feedlot steer performance and carcass characteristics.

Three experiments were conducted to compare the feeding value of genetically enhanced corn (Roundup Ready corn events GA21 and nk603) with nontransgenic hybrids. The four treatments included two separate reference hybrids (REF), the near-isogenic control hybrid (CON), and the genetically enhanced corn (RR), resulting in two preplanned comparisons of CON vs. RR and RR vs. the average of REF. In Exp. 1 (RR event GA21), 175 steers (BW = 427 kg) were fed in 25 pens with seven pens per corn hybrid, except CON, which contained four pens due to limited quantities of that hybrid. In Exp. 2 (RR event nk603), 196 steers (BW = 420 kg) were fed in 28 pens with seven pens per corn. In Exp. 3 (RR event nk603), 200 steers were fed in 20 pens, with a similar treatment design to Exp. 2 and five pens per corn. All experiments were conducted as completely randomized designs and utilized corn produced at University of Illinois (Exp. 1 and 2) and University of Nebraska (Exp. 3) research farms under identity-preserved protocols. In all experiments, DMI, ADG, and feed efficiency were similar (P > 0.30) between RR and REF. In Exp. 1 and Exp. 2, RR was not different (P > 0.25) than CON for growth performance. In Exp. 3, RR was not different from CON for ADG and DMI (P > 0.15) or for feed efficiency (P = 0.08). No differences were observed between RR and CON or RR and REF for carcass weight, longissimus dorsi area, and marbling scores in any of the experiments. Subtle differences were observed between RR and either CON or REF for fat depth in each experiment; however, cattle fed RR were not consistently greater and varied from either the CON or the REF (but not both contrasts) within an experiment. Based on these results, insertion of glyphosate-tolerant genes had no significant effect on nutritive quality of corn. Performance and carcass characteristics were not influenced, which suggests that Roundup Ready corn is similar to conventional, nontransgenic corn when fed to finishing feedlot cattle.

Animal Feed↗

PubMed2005

Corn grain endosperm type and brown midrib 3 corn silage: feeding behavior and milk yield of lactating cows.

Interactions of endosperm type of corn grain and the brown midrib 3 mutation (bm3) in corn silage on feeding behavior, productivity, energy balance, and plasma metabolites of lactating dairy cows were evaluated. Eight ruminally and duodenally cannulated cows (72 +/- 8 d in milk; mean +/- SD) were used in a duplicated 4 x 4 Latin square design experiment with a 2 x 2 factorial arrangement of treatments. Treatments were corn grain endosperm type (floury or vitreous), and corn silage type (bm3 or isogenic control). Diets contained 26% neutral detergent fiber (NDF) and 30% starch. Floury endosperm grain decreased dry matter intake (DMI) 1.9 kg/ d compared with vitreous grain when combined with control corn silage but did not affect DMI when combined with bm3 corn silage. This interaction of treatments occurred because of changes in meal size; floury endosperm grain decreased meal size in control silage diets but increased meal size in bm3 corn silage diets. Ruminal pool sizes reflected DMI differences among diets, suggesting that ruminal fill was not the primary limitation on intake. Brown midrib 3 corn silage reduced rumination time per day and number of rumination bouts per day. Floury endosperm grain decreased 3.5% fat-corrected milk by 1.2 kg/d when combined with control silage but increased 3.5% fat-corrected milk by 2.1 kg/d when combined with bm3 corn silage. Starch and fiber digestibility interact to affect feeding behavior and milk production and production response to bm3 corn silage depends on the grain source that is fed.

Animals↗

PubMed2003

M-CSF induces vascular endothelial growth factor production and angiogenic activity from human monocytes.

The impact of the immune response in malignancy is poorly understood. While immune cells can destroy transformed cells, the targeting and accumulation of monocytes and macrophages at tumor sites may promote tumor metastases. The growth factor M-CSF is important in promoting monocyte survival. Since M-CSF(-/-) mice are protected against tumor metastases, we hypothesized that M-CSF induced monocytes to produce angiogenic factors that facilitate metastases. In this study we demonstrate that recombinant human M-CSF induces freshly isolated normal human monocytes to produce and release the growth factor vascular endothelial growth factor (VEGF) in a dose-dependent manner, which peaked at 5 days in culture. VEGF released by these monocytes is biologically active, as cell-free supernatants from these M-CSF-stimulated monocytes induced tube formation in HUVEC. Network formation by these HUVECs after treatment with supernatants from monocytes stimulated with M-CSF were inhibited by anti-VEGF, but not by the isogenic control, Abs. Collectively, these data support an important role for M-CSF and monocytes in VEGF production and angiogenesis.

Angiogenesis Inducing Agents↗

PubMed2000

The transcription factor DBP affects circadian sleep consolidation and rhythmic EEG activity.

Albumin D-binding protein (DBP) is a PAR leucine zipper transcription factor that is expressed according to a robust circadian rhythm in the suprachiasmatic nuclei, harboring the circadian master clock, and in most peripheral tissues. Mice lacking DBP display a shorter circadian period in locomotor activity and are less active. Thus, although DBP is not essential for circadian rhythm generation, it does modulate important clock outputs. We studied the role of DBP in the circadian and homeostatic aspects of sleep regulation by comparing DBP deficient mice (dbp-/-) with their isogenic controls (dbp+/+) under light-dark (LD) and constant-dark (DD) baseline conditions, as well as after sleep loss. Whereas total sleep duration was similar in both genotypes, the amplitude of the circadian modulation of sleep time, as well as the consolidation of sleep episodes, was reduced in dbp-/- under both LD and DD conditions. Quantitative EEG analysis demonstrated a marked reduction in the amplitude of the sleep-wake-dependent changes in slow-wave sleep delta power and an increase in hippocampal theta peak frequency in dbp-/- mice. The sleep deprivation-induced compensatory rebound of EEG delta power was similar in both genotypes. In contrast, the rebound in paradoxical sleep was significant in dbp+/+ mice only. It is concluded that the transcriptional regulatory protein DBP modulates circadian and homeostatic aspects of sleep regulation.

Animals↗

PubMedDate not supplied

[Effect of factors from the Chernobyl exclusion zone on the level of cytochrome P-450 in mouse liver microsomes].

The data concerning the influence of Chernobyl exclusive zone factors on cytochrome P-450 relative contents in liver microsome fractions of Balb/c, CC57W/Mv and C57 Black mice are submitted in this work Reliable diminishing of liver P-450 relative concentration in experimental animals, compared with respective isogenic control groups is shown to be varying depending on the mouse line and sex.

Animals↗

PubMed2001

Antitumor activity of 2',3'-dideoxycytidine nucleotide analog against tumors up-regulating DNA polymerase beta.

DNA polymerase beta (Pol beta), an error-prone DNA-synthesizing enzyme tightly down-regulated in healthy somatic cells, has been shown to be overexpressed in many human tumors. In this study, we show that treatment with the 2',3'-dideoxycytidine (ddC) nucleoside analog inhibited in vitro and in vivo the proliferation of Pol beta-transfected B16 melanoma cells, which up-regulate Pol beta compared with control isogenic cells. The administration of ddC also increased specifically the survival of mice bearing Pol beta-overexpressing B16 melanoma. When the phosphorylated form of ddC was electrotransfered into Pol beta-transfected melanoma, the cell growth inhibition was strengthened, strongly suggesting that the cytotoxic effect results from incorporation of the chain terminator into DNA. Using in vitro single- and double-stranded DNA synthesis assays, we demonstrated that excess Pol beta perturbs the replicative machinery, favors ddC-TP incorporation into DNA, and consequently promotes chain termination. Therefore, the use of chain terminator anticancer agents could be suitable for the treatment of tumors with a high level of Pol beta.

Animals↗

PubMed1982

Isolation and characterization of an Escherichia coli mutant lacking tRNA-guanine transglycosylase. Function and biosynthesis of queuosine in tRNA.

An E. coli mutant that lacks tRNA-guanine transglycosylase was isolated by random screening from a collection of Escherichia coli mutants obtained with N-methyl-N'-nitro-N-nitrosoguanidine. The defective gene, named tgt, was mapped at about 9 min on the E. coli chromosome, and the gene order was shown to be phoB-tgt-tsx. tgt was transferred to an E. coli strain with a defined genetic background by P1 transduction to investigate its function. The mutant thus obtained lacked queuosine (2-amino-5-[3S, 4R, 5S)-4,5-dihydroxycyclopent-1-en-3-ylaminomethyl]-7-(beta-D-ribofuranosyl)-pyrro lo-[2,3-D]-pyrimidin-4-one) in tRNA, indicating that the enzyme is actually involved in the biosynthesis of queuosine in tRNA. No clear biological defect was observed in the mutant, and, in fact, it grew slightly faster than the control isogenic strain. tRNATyr lacking queuosine, isolated from the mutant, showed no significant biological difference from normal queuosine-containing tRNA in amino acid acceptor activity or amino acid transfer in a cell-free protein synthesizing system directed by synthetic polynucleotide. The only phenotypic change observed in the mutant thus far is marked reduction of viability when the cells are kept under unsuitable conditions for growth, suggesting that the presence of queuosine in tRNA is important to E. coli for survival in the natural environment.

Escherichia coli↗

PubMed1997

[Hyperrecombination of plasmids is characteristic for hyperresistant strains of Escherichia coli].

Intraplasmid recombination frequency was assessed in several Escherichia coli K12 strains by the kinetic bioluminescence method. Enhanced plasmid recombination was observed in two mutant E. coli K12 strains, which were hyperresistant to DNA-damaging agents, gamma-rays, photosensitizer 8-methoxypsoralen. Plasmid recombination frequency per one generation (P) was calculated. In mutant strains, this value was shown to exceed that in control isogenic strains with a standard resistance approximately by a factor of 15. Enhanced constitutive synthesis of specific proteins such as heat-shock proteins in Gamr444 and a 55-kDa protein in SA270 in hyperresistant mutant strains is assumed to promote activity of the recombinational RecF pathway system.

DNA Damage↗

PubMed1998

p53-dependent signaling sustains DNA replication and enhances clonogenic survival in 254 nm ultraviolet-irradiated human fibroblasts.

The cyclin-dependent kinase inhibitor p21(WAF1/CIP1/SDI1/CAP20) exists in normal human fibroblasts in a quaternary complex with a cyclin, a cyclin-dependent kinase, and proliferating cell nuclear antigen. A model was proposed in which, during p53-mediated suppression of cell proliferation following treatment with 254 nm UV radiation (UVC), the enhanced expression of p21 might inhibit DNA replication by virtue of its interactions with proliferating cell nuclear antigen. To test this model, we examined the mechanisms of inhibition of DNA replication in diploid human fibroblasts that express human papillomavirus type 16 E6, which inactivates p53. E6-expressing cells were defective in G1 checkpoint responses of induction of p21 and G1 arrest after ionizing radiation-induced damage to DNA. Accordingly, E6-expressing cells were resistant to inactivation of single-cell colony formation by ionizing radiation. E6 cells also displayed normal S-phase checkpoint responses of inhibition and recovery of replicon initiation following exposure to ionizing radiation and normal ability to bypass pyrimidine dimers during DNA replication soon after UVC irradiation (i.e., postreplication repair). However, DNA replication 6 h after UVC exposure was significantly inhibited in E6 cells in comparison to isogenic controls. This failure to maintain DNA replication in S-phase cells was associated with enhanced sensitivity to inactivation of single-cell colony formation by UVC. These results indicate that the p53-induced p21 pathway is not involved in the immediate S-phase responses to radiation-induced DNA damage of inhibition of replicon initiation and translesion bypass. However, our results demonstrate that p53 and, conceivably, p21 contribute to the ability of normal human fibroblasts to sustain DNA replication activity and form colonies following UVC irradiation.

Cell Line↗

PubMed2026

Establishment of human induced pluripotent stem cell lines and isogenic gene-corrected controls from three patients with prolidase deficiency.

Prolidase deficiency is an autosomal recessive inborn error of metabolism caused by pathogenic variants in the PEPD gene. To date, close to 200 patients have been reported worldwide with a poorly understood pathomechanism. The PEPD gene encodes an enzyme that is involved in the final steps of collagen degradation. Urine amino acid analysis or specific dipeptide analysis can establish the biochemical diagnosis. In this study, we reprogrammed peripheral blood mononuclear cells (PBMCs) from three prolidase deficient patients into induced pluripotent stem cell (iPSC) lines and additionally generated isogenic controls using CRISPR-Cas9 genome editing. The pathogenic PEPD variants identified in our patients were NP_000276.2:p.? (NIHTVBi032-A), NP_000276.2:p.(Ile415Asn)/NP_000276.2:p.(Trp326Ter) (NIHTVBi033-A), and NP_000276.2:p.(Arg265Ter) (NIHTVBi034-A). These iPSC lines are valuable models to help investigate the pathomechanism of prolidase deficiency.

Humans↗

PubMed2005

Effects of grazing residues or feeding corn from a corn rootworm-protected hybrid (MON 863) compared with reference hybrids on animal performance and carcass characteristics.

One grazing and two feeding experiments were conducted to compare the feeding value of corn residue or corn grain from a genetically enhanced corn hybrid (corn rootworm-protected; event MON 863) with nontransgenic, commercially available, reference hybrids. In Exp. 1, two 13.7-ha fields, containing corn residues from either a genetically enhanced corn root-worm-protected hybrid (MON 863), or a near-isogenic, nontransgenic control hybrid (CON) were divided into four equal-sized paddocks. Sixty-four steer calves (262 +/- 15 kg) were stratified by BW and assigned randomly to paddock to achieve a stocking rate of 0.43 ha/steer for 60 d, with eight steers per paddock and 32 steers per hybrid. A protein supplement was fed at 0.45 kg/steer daily (DM basis) to ensure protein intake did not limit performance. Steer ADG did not differ (P = 0.30) between steers grazing the MON 863 (0.39 kg/d) and CON (0.34 kg/d) corn residues for 60 d. The four treatments for the feeding experiments (Exp. 2 and 3) included two separate reference hybrids, the near-isogenic control hybrid (CON), and the genetically enhanced hybrid (MON 863) resulting in two preplanned comparisons of CON vs. MON 863, and MON 863 vs. the average of the reference hybrids (REF). In Exp. 2, 200 crossbred yearling steers (365 +/- 19 kg) were fed in 20 pens, with five pens per corn hybrid. In Exp. 3, 196 crossbred yearling steers (457 +/- 33 kg) were fed in 28 pens, with seven pens per corn hybrid. In Exp. 2, DMI and G:F did not differ (P > 0.10) between MON 863 and CON; however, steers fed MON 863 had a greater (P = 0.04) ADG than steers fed CON. Gain efficiency was greater (P = 0.05) for MON 863 cattle than for REF cattle in Exp. 2, but other performance measurements (DMI and ADG) did not differ (P > 0.10) between MON 863 and REF. No differences (P > 0.10) were observed for performance (DMI, ADG, and G:F) between MON 863 and CON or MON 863 and REF in Exp. 3. In terms of carcass characteristics, no differences (P > 0.10) were observed between MON 863 and CON, as well as MON 863 and REF, for marbling score, LM area, or 12th rib fat thickness in both Exp. 2 and 3. Overall, performance was not negatively affected in the corn residue grazing or feedlot experiments, suggesting the corn rootworm-protected hybrid (event MON 863) is similar to conventional, nontransgenic corn grain and residues when utilized by beef cattle.

Animal Feed↗

PubMed1980

Alteration of Escherichia coli murein during amino acid starvation.

We have studied the mechanisms by which amino acid starvation of Escherichia coli induces resistance against the lytic and bactericidal effects of penicillin. Starvation of E. coli strain W7 of the amino acids lysine or methionine resulted in the rapid development of resistance to autolytic cell wall degradation, which may be effectively triggered in growing bacteria by a number of chemical or physical treatments. The mechanism of this effect in the amino acid-starved cells involved the production of a murein relatively resistant to the hydrolytic action of crude murein hydrolase extracts prepared from normally growing E. coli. Resistance to the autolysins was not due to the covalently linked lipoprotein. Resistance to murein hydrolase developed most rapidly and most extensively in the portion of cell wall synthesized after the onset of amino acid starvation. Lysozymes digests of the autolysin-resistant murein synthesized during the first 10 min of lysine starvation yielded (in addition to the characteristic degradation products) a high-molecular-weight material that was absent from the lysozyme-digests of control cell wall preparations. It is proposed that inhibition of protein synthesis causes a rapid modification of murein structure at the cell wall growth zone in such a manner that attachment of murein hydrolase molecules is inhibited. The mechanism may involve some aspects of the relaxed control system since protection against penicillin-induced lysis developed much slower in amino acid-starved relaxed controlled (relA) cells than in isogenic stringently controlled (relA+) bacteria.

Amino Acids↗

PubMed1999

Modulation of force-frequency relation by phospholamban in genetically engineered mice.

Phospholamban levels regulate cardiac sarcoplasmic reticulum Ca2+ pump activity and myocardial contractility. To determine whether and to what extent phospholamban modulates the force-frequency relation and ventricular relaxation in vivo, we studied transgenic mice overexpressing phospholamban (PLBOE), gene-targeted mice without phospholamban (PLBKO), and isogenic wild-type controls. Contractility was assessed by the peak rate of left ventricular (LV) isovolumic contraction (+dP/dtmax), and diastolic function was assessed by both the peak rate (-dP/dtmax) and the time constant (tau) of isovolumic LV relaxation, using a high-fidelity LV catheter. Incremental atrial pacing was used to generate heart rate vs. -dP/dtmax (force-frequency) relations. Biphasic force-frequency relations were produced in all animals, and the critical heart rate (HRcrit) was taken as the heart rate at which dP/dtmax was maximal. The average LV +dP/dtmax increased in both PLBKO and PLBOE compared with their isogenic controls (both P < 0.05). The HRcrit for LV +dP/dtmax was significantly higher in PLBKO (427 +/- 20 beats/min) compared with controls (360 +/- 18 beats/min), whereas the HRcrit in PLBOE (340 +/- 30 beats/min) was significantly lower compared with that in isogenic controls (440 +/- 25 beats/min). The intrinsic heart rates were significantly lower, and the HRcrit and the +/-dP/dtmax at HRcrit were significantly greater in FVB/N than in SvJ control mice. We conclude that 1) the level of phospholamban is a critical negative determinant of the force-frequency relation and myocardial contractility in vivo, and 2) contractile parameters may differ significantly between strains of normal mice.

Animals↗

PubMed1999

Reduced interleukin-8 production by cystic fibrosis airway epithelial cells.

The acquisition of Pseudomonas aeruginosa in the airways of patients with cystic fibrosis (CF) is the initial event leading to bronchiectasis and lung disease. Although the host factors that permit initial airway colonization are largely unknown, recent studies suggest that secretion of interleukin (IL)-8 by airway epithelia and local recruitment of neutrophils is the final pathway in a pulmonary cytokine network. To determine whether differences in cytokine production exist between normal and CF airway epithelia, secretion of immunoreactive IL-8 and IL-10 as well as specific messenger RNA (mRNA) abundance were compared in airway epithelia expressing normal and mutant CF transmembrane regulator. After induction with IL-1beta, a CF airway cell line engineered to express the wild-type CF gene (CFT1-LCFSN) secreted significantly more immunoreactive IL-8 than did its isogenic parent that expressed the mutant CF gene (CFT1) or an isogenic vector control line (CFT1-LC3). Further studies with the three related cell lines demonstrated that expression of CFT1-LCFSN was associated with a significant increase in uninduced secretion of immunoreactive IL-8 as well as a 10- to 20-fold increase in IL-8 mRNA abundance when compared with the isogenic lines expressing the mutant gene. IL-1beta induction and intracellular accumulation of IL-8 appeared to be unaffected by CF genotype. These studies suggest that IL-8 secretion by CF airway epithelial cells is defective and may contribute to Pseudomonas persistence in the CF airway. Further studies are needed to confirm this difference in other cell lines and determine the linkage between IL-8 production and CF gene expression.

Bronchi↗