Potential genetic modifiers of the cystic fibrosis intestinal inflammatory phenotype on mouse chromosomes 1, 9, and 10
© Norkina and De Lisle; licensee BioMed Central Ltd. 2005
Received: 17 January 2005
Accepted: 27 May 2005
Published: 27 May 2005
Although cystic fibrosis is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, the severity of disease is highly variable indicating the influence of modifier genes. The intestines of Cftr deficient mice (CF mice: Cftrtm 1Unc) are prone to obstruction by excessive mucus accumulation and are used as a model of meconium ileus and distal intestinal obstruction syndrome. This phenotype is strongly dependent on the genetic background of the mice. On the C57Bl/6 background, the majority of CF mice cannot survive on solid mouse chow, have inflammation of the small intestine, and are about 30% smaller than wild type littermates. In this work potential modifier loci of the CF intestinal phenotype were identified.
CF mice on a mixed genetic background (95% C57Bl/6 and 5% 129Sv) were compared to CF mice congenic on the C57Bl/6 background for several parameters of the intestinal CF phenotype. CF mice on the mixed background exhibit significantly greater survival when fed dry mouse chow, have reduced intestinal inflammation as measured by quantitative RT-PCR for marker genes, have near normal body weight gain, and have reduced mucus accumulation in the intestinal crypts. There was an indication of a gender effect for body weight gain: males did not show a significant improvement at 4 weeks of age, but were of normal weight at 8 weeks, while females showed improvement at both 4 and 8 weeks. By a preliminary genome-wide PCR allele scanning, three regions were found to be potentially associated with the milder phenotype. One on chr.1, defined by marker D1Mit36, one on chr. 9 defined by marker D9Mit90, and one on chr. 10, defined by marker D10Mit14.
Potential modifier regions were found that have a positive impact on the inflammatory phenotype of the CF mouse small intestine and animal survival. Identification of polymorphisms in specific genes in these regions should provide important new information about genetic modifiers of the CF intestinal phenotype.
Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene . Different mutations have a range of effects on the levels of CFTR protein and its proper functioning in epithelial transport of Cl- and HCO3- [2, 3]. The severity of the pancreatic phenotype in human CF is well correlated with the extent of impaired CFTR function caused by specific mutations. Loss of CFTR function results in destruction of the exocrine tissue and eventual pancreatic insufficiency. On the other hand, the effects of CF on organs including the airways and intestines is less well correlated with specific CFTR mutations and their effects on CFTR protein function [4–8]. This indicates that other genes are likely to be important as modifiers of the CF phenotype.
With the exception of pancreatic insufficiency resulting in impaired digestion, other aspects of CF are less readily related to loss of CFTR function. Nutritional problems can persist even with adequate oral enzyme supplementation  and neutralization of gastric acid to improve lipase function , and may involve both impaired digestion and absorption of nutrients . Inadequate absorption or assimilation of nutrients appears to be of greater importance because even with adequate oral enzyme supplementation nutrition is rarely fully corrected . There is also excessive mucus accumulation in the CF intestine, and inappropriate inflammation is common . Mucus is involved in obstruction of the gut which occurs frequently in CF infants (called meconium ileus, MI) and adults (called distal intestinal obstruction syndrome, DIOS) [11, 13]. And, similar to CF airways, there is also an inflammation of the CF intestines [14, 15]. These changes are less directly related to specific mutations in the CFTR gene and are likely related to other differences in individual genetic makeup.
Previous work using human patients and genetically altered mice has identified some modifier genes and have advanced our understanding of CF pathophysiology . In one study using CF mice on different genetic backgrounds, a region on mouse chromosome 7 was shown to ameliorate intestinal blockage and the effect was in part due to a calcium-regulated Cl-channel which compensated for loss of CFTR function [16, 17]. Marker haplotypes of the syntenic region of human chromosome 19q13 were also shown to be associated with the risk of MI in CF patients . In other work, a region on mouse chr. 6 was strongly associated with lung inflammation, consisting of mononuclear cell interstitial infiltration and fibrosis in CF mouse airways; and other loci on chr. 1, 2, 10, and 17 were also linked to the airway phenotype .
In this work, CF mice on a mixed strain background were found to have a less severe CF phenotype compared to CF mice congenic on the C57Bl/6 background. There were no differences in the pancreatic phenotype comparing CF mice on the different backgrounds . However, mice on the mixed background seemed more robust than CF mice on the B6 background which prompted us to characterize them in greater detail. Genome wide allele scanning was used to begin identification of regions associated with the less severe intestinal phenotype. Future identification of specific genes should further our understanding of the complex intestinal CF phenotype.
Results and discussion
CF mice on the mixed background have improved body weight gain
CF mice on the mixed background have reduced expression of inflammatory markers
Previous work showed that CF mice on the B6 background have an innate-type inflammation of the small intestine . To determine whether the mixed genetic background affected expression of inflammatory marker genes, quantitative, real-time RT-PCR was used to measure gene expression. Expression of the following genes was compared in wild type and CF mice on the different genetic backgrounds. Mast cell protease 2 (Mcpt2) is a marker of differentiated mast cells  and mast cells are more abundant in the B6 CF mouse intestine. Leucine-rich α2 glycoprotein (Lrg1, ) is a marker of differentiating neutrophils, which are more numerous in the B6 CF mouse intestine. The same gene is also known as leucine-rich high endothelial cell glycoprotein (Lrhg) and has been shown to be a marker of high endothelial venules (HEV)  which increase in tissues during inflammation [25, 26]. Hematopoietic cell transcript 1 (HemT1, ) is a marker of blood cell proliferation and its expression is strongly elevated in the B6 CF mouse small intestine. Serum amyloid A3 (SAA3, ) is an acute phase gene and its expression in villus epithelial cells is increased in the B6 CF intestine. Suppressor of cytokine signaling 3 (SOCS3, ) is an anti-inflammatory gene that interacts with the JAK-STAT pathway and its expression in increased in the B6 CF intestine. Muclin (also known as dmbt1, ) expression is upregulated in the B6 CF intestine; it is a cell surface glycoprotein postulated to be an epithelial protective molecule [21, 31].
Because of the gender differences in body weight, the gene expression data were analyzed by gender but there was no significant difference between females and males. With the limited number of animals, there was also no evidence for imprinting.
CF mice on the mixed background have less intestinal mucus accumulation
Thus, it appears that whatever the nature of the genetic differences between the two background strains, they affect secretion and accumulation of mucus in the CF small intestine. To determine if the difference could be accounted for by altered mucin gene expression, quantitative RT-PCR was used to measure mRNA expression of the intestinal goblet cell mucin gene, Muc2. In wild type intestine, B6 mice had 0.079 +/- 0.024 copies of Muc2/GAPDH (n = 8), and on the mixed background the level was 0.077 +/- 0.012 (n = 11). CF mice on the B6 background had 0.059 +/- 0.024 copies of Muc2 mRNA per GAPDH (n = 11), and on the mixed background the level was 0.056 +/- 0.010 (n = 11). Despite the increased mucus accumulation in CF, there is a slight decrease in Muc2 mRNA in the CF small intestine (P < 0.0001), as previously reported . However, the milder CF phenotype on the mixed background, which includes less mucus accumulation, does not involve decreased mucin gene expression.
CF mice on the mixed background have improved survival
Distribution of Cftr genotypes in female offspring from breeding Cftr heterozygotes on the B6 and mixed backgrounds.
Distribution of Cftr genotypes in male offspring from breeding Cftr heterozygotes on the B6 and mixed backgrounds.
Identification of potential modifier loci
To determine the contributions of B6 and 129 alleles to the mixed genetic background, and to identify potential modifier regions, tail DNA was analyzed by PCR for markers of polymorphisms between these two mouse strains. Mice congenic on the B6 background, which were derived from mice originally on a B6/129 mixed background, were also analyzed to confirm they are congenic B6. Twelve CF mice on the B6 background averaged 99.5% B6 alleles. One of the twelve mice had alleles from both strains at chr.9, 40 cM. All twelve mice had both B6 and 129 markers on chromosome 6, 1 cM which is probably due to the targeted Cftr gene which is at chr.6, 3.1 cM .
Genome scanning analysis of CF mice on the mixed background.
Number of Mice
Because the spacing of markers used was about 12 cM, genes within 75% of this interval on either side of the markers were looked at for potential relevance to the milder CF intestinal phenotype. None of the known chloride channels that might substitute for the missing CFTR are in the regions of the three chromosomes associated with the milder phenotype. There are several potassium channel genes in the identified regions that potentially could affect electrolyte and fluid transport: Kcnj9 (chr.1, 94.2 cM), Kcnj10 (chr.1, 93.5 cM), Kcnj5 (chr.9, 11 cM), and Kcnc2 (chr.10, 62 cM). All gene names are from the Mouse Genome Informatics website http://www.informatics.jax.org.
Inflammation is a hallmark of CF, and whether there is an inherent defect in CF that predisposes to excessive inflammation is controversial. Several genes involved in inflammation and the immune system are located in the regions of the markers identified: TNF superfamily members Tnfsf4, 6, and 8 (chr.1, 84.9–85 cM) which are involved in T cell activation [37, 38]; three selectin genes (Sele, Sell, Selp, chr.1, 86.6 cM) which are involved in immune cell infiltration into inflamed tissues ; several members of immune cell surface proteins of the Slam family (slamf1, 2, 5, 6, and 9; chr.1, 89.5–93.3 cM) ; the chemokine gene Xcl1 (chr.1, 87 cM) which is expressed by mast cells and recruits lymphocytes ; several immunoglobulin Fc receptor genes (Fcrl3, Fcgr2b, and Fcgr3 at chr.1, 92.3 cM; Fcer1g at chr.1, 93.3 cM; Fcer1a at chr.1, 94.2 cM); the flagellin receptor Tlr5 (chr.1, 98 cM); Mmp3 (chr.9, 1 cM) which recruits CD4+ lymphocytes ; Mmp7 (chr.9, 1 cM) which activates Paneth cell-derived cryptdins (α-defensins) ; Icam1 (chr.9, 7 cM) which is involved in lymphocyte infiltration into inflamed tissues ; Kitl (chr.10, 57 cM) which is also known as stem cell factor, and is crucial for mast cell differentiation ; Im5 (chr.10, 65 cM) which is involved in antibody-responsiveness ; Lyzs (chr.10, 66 cM) which is a Paneth cell product that digests cell walls of bacteria ; Ifng (chr.10, 67 cM) which is an important inflammatory signal in CF as well as other conditions ; Il22 (chr.10, 67 cM), a member of the anti-inflammatory IL-10 interleukin family ; and the Stat2 and 6 genes (chr.10, 70 cM) which are important components of intracellular signaling pathways .
Also near the identified markers are a number of QTL associated with body weight: Cfbw1, CF mouse body weight at chr.1, 85 cM; Obq9, obesity 9 at chr.1, 88 cM; Bw8q1, body weight 8 at chr.1, 100 cM; Lbm6, lean body mass 6 at chr.9, 7.7 cM; Bwtq4, body weight 4 at chr.9, 8 cM; Bgeq8, body growth early 8 at chr.10, 57 cM; and Pbwg5, postnatal body weight growth 5 at chr.10, 68 cM.
Clearly, there are numerous genes in the three regions identified in this study. Because the CF mouse intestinal phenotype is characterized by an innate type immune response, with increases in mast cells and neutrophils, the genes that affect these cells are of special interest. The Kitl gene is crucial for differentiation of mast cells, and CF mice on the mixed background have much fewer mature mast cells than on the B6 background as revealed by less expression of Mcpt2. Similarly, for neutrophils the selectins and Icam1 are of interest, as these proteins are required for extravasation of neutrophils from the circulation into the inflamed tissue.
Altered immune responses may also relate to excessive mucus accumulation in the CF intestine. It is unclear why mucus accumulates to high levels in CF tissues. In part it may be due to reduced fluid secretion and a more acidic environment in the lumina of affected organs. However, there is also evidence for hypersecretion of mucus in CF , and it is likely that effector molecules released by mast cells and neutrophils (histamine, proteases, prostaglandins) have an important role in stimulating mucus secretion.
This work demonstrated that the CF inflammatory phenotype is much less severe in mice with a small contribution of 129/Sv alleles. A preliminary analysis identified regions on chr.1, 9, and 10 are that are potentially associated with the milder phenotype. Because of the inflammation of the CF small intestine, and the possible effects of immune cells on mucus secretion, the genes in the identified regions which are involved in mast cell and neutrophil differentiation and behavior are of special interest as potential CF modifiers. Future work should focus on narrowing down these regions and determining if there are polymorphisms that affect expression of specific genes that make the CF intestinal phenotype less severe.
Wild type and Cftr null mice on two different genetic backgrounds were used in this study. One group was congenic on the C57Bl/6 (B6) background, as previously described . The other group was on a mixed background of about 95% B6 and 5% 129/Sv (129). The mice on the mixed background originated as part of a recently published study  as follows. Mice carrying a targeted mutation of the gastrin gene on a mixed B6/129 background  were bred for eight generations onto the B6 background. The gastrin(+/-) mice were then crossed for six generations with Cftr(+/-) mice congenic on the B6 background. A genome scan at this point showed that the mice were about 95% B6 and 5% 129 (see below). These mice were bred to obtain mice wild type for both gastrin alleles and either Cftr homozygous wild type [Cftr(+/+)] or Cftr homozygous null [Cftr(-/-)].
Mice were genotyped at 2 weeks of age by PCR as previously described . Unless otherwise stated, mice were maintained on a complete elemental liquid diet (Peptamen; Nestle Deerfield, IL) to prevent intestinal obstruction that occurs in CF mice . Wild type littermates were maintained on the same diet. In some experiments, 8 week old mice were transferred onto solid mouse chow instead of Peptamen, and survival was recorded. Mice with apparent distress were sacrificed and survival on chow was recorded as the following day. Male and female mice were used at 6–16 weeks of age. Mice were kept in a specific pathogen-free facility in barrier-top cages. All procedures were approved by the University of Kansas Medical Center IACUC.
Genetic background determination
The Genome Scanning Service of The Jackson Laboratory (Bar Harbor, ME) was used to determine the contributions of C57Bl/6 and 129/Sv strains in the interbred mice. Pieces of mouse tail were sent to The Jackson Laboratory for simple sequence length polymorphism (SSLP) PCR analysis with the DMit primers specific for B6 and 129 strain alleles http://www.jax.org. The SSLP panel consists of 108 mapped markers designed to distinguish between B6 and 129 strains. The markers are spaced 12–13 cM apart and span the nineteen autosomes.
Measurement of gene expression
Total RNA was extracted from the entire small intestine as previously described . Quantitative, real-time RT-PCR was used to measure expression of specific genes using the previously described primers . Values were normalized to GAPDH mRNA and expression of this housekeeping gene is not altered in the CF mouse small intestine . Expression of the major intestinal mucin, Muc2, was also measured using the forward (5'-GAC TTC GAT GGA CAC TGC TC-3') and reverse (5'-CAC GGT GTT TAT CTA CCA AC-3') primers.
The small intestine was flushed with phosphate buffered saline and immersion fixed overnight in 4% paraformaldehyde. The tissues were then prepared for paraffin embedding and sectioning by a commercial service (HSRL, Woodstock, VA). Sections (5 μm) were stained with periodic acid Schiff's (PAS) for neutral mucins.
Gene expression and body weight data were compared by ANOVA with a post-hoc Tukey's analysis (Systat software, Chicago, IL). Survival data were analyzed by a log-rank test for P values (PEPI software, http://www.brixtonhealth.com/). The distributions of genotypes of pups surviving to weaning from breeding Cftr(+/-) mice were compared to that expected by Mendelian genetics using Chi-square analysis. For all statistical tests, P < 0.05 was considered significant.
We thank Larysa Stroganova for maintenance of the mouse colonies and PCR genotyping. Supported by National Institutes of Health grant DK 56791.
- Riordan JR, Rommens JM, Kerem BS, Alon N, Rozmahel R, Grzelczak Z, Zielenski J, Lok S, Plavsic N, Chou JL, Drumm ML, Iannuzzi MC, Collins FS, Tsui LC: Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA. Science. 1989, 245: 1066-1073.View ArticlePubMed
- Choi JY, Muallem D, Kiselyov K, Lee MG, Thomas PJ, Muallem S: Aberrant CFTR-dependent HCO3- transport in mutations associated with cystic fibrosis. Nature. 2001, 410: 94-97. 10.1038/35065099.PubMed CentralView ArticlePubMed
- Clarke LL, Harline MC: Dual role of CFTR in cAMP-stimulated HCO3- secretion across murine duodenum. Am J Physiol. 1998, 274: G718-G726.PubMed
- Davies JC: Modifier genes in cystic fibrosis. Pediatr Pulmonol. 2004, 86-87. 10.1002/ppul.70062. Suppl 26
- Merlo CA, Boyle MP: Modifier genes in cystic fibrosis lung disease. J Lab Clin Med. 2003, 141: 237-241. 10.1067/mlc.2003.29.View ArticlePubMed
- Accurso FJ, Sontag MK: Seeking modifier genes in cystic fibrosis. Am J Respir Crit Care Med. 2003, 167: 289-290. 10.1164/rccm.2210006.View ArticlePubMed
- Rowntree RK, Harris A: The phenotypic consequences of CFTR mutations. Ann Hum Genet. 2003, 67: 471-485. 10.1046/j.1469-1809.2003.00028.x.View ArticlePubMed
- Salvatore F, Scudiero O, Castaldo G: Genotype-phenotype correlation in cystic fibrosis: the role of modifier genes. Am J Med Genet. 2002, 111: 88-95. 10.1002/ajmg.10461.View ArticlePubMed
- Dray X, Kanaan R, Bienvenu T, Desmazes-Dufeu N, Dusser D, Marteau P, Hubert D: Malnutrition in adults with cystic fibrosis. Eur J Clin Nutr. 2005, 59: 152-4. 10.1038/sj.ejcn.1602039.View ArticlePubMed
- Proesmans M, De Boeck K: Omeprazole, a proton pump inhibitor, improves residual steatorrhoea in cystic fibrosis patients treated with high dose pancreatic enzymes. Eur J Pediatr. 2003, 162: 760-763. 10.1007/s00431-003-1309-5.View ArticlePubMed
- Mascarenhas MR: Treatment of Gastrointestinal Problems in Cystic Fibrosis. Curr Treat Options Gastroenterol. 2003, 6: 427-441.View ArticlePubMed
- Jeffery P, Zhu J: Mucin-producing elements and inflammatory cells. Novartis Found Symp. 2002, 248: 51-68.View ArticlePubMed
- Dray X, Bienvenu T, Desmazes-Dufeu N, Dusser D, Marteau P, Hubert D: Distal intestinal obstruction syndrome in adults with cystic fibrosis. Clin Gastroenterol Hepatol. 2004, 2: 498-503. 10.1016/S1542-3565(04)00169-7.View ArticlePubMed
- Smyth RL, Croft NM, O'Hea U, Marshall TG, Ferguson A: Intestinal inflammation in cystic fibrosis. Arch Dis Child. 2000, 82: 394-399. 10.1136/adc.82.5.394.PubMed CentralView ArticlePubMed
- Raia V, Maiuri L, De Ritis G, De Vizia B, Vacca L, Conte R, Auricchio S, Londei M: Evidence of chronic inflammation in morphologically normal small intestine of cystic fibrosis patients. Pediatr Res. 2000, 47: 344-350.View ArticlePubMed
- Rozmahel R, Wilschanski M, Matin A, Plyte S, Oliver M, Auerbach W, Moore A, Forstner J, Durie P, Nadeau J, Bear C, Tsui LC: Modulation of disease severity in cystic fibrosis transmembrane conductance regulator deficient mice by a secondary genetic factor. Nature Genet. 1996, 12: 280-287. 10.1038/ng0396-280.View ArticlePubMed
- Gyömörey K, Rozmahel R, Bear CE: Amelioration of intestinal disease severity in cystic fibrosis mice is associated with improved chloride secretory capacity. Pediatr Res. 2000, 48: 731-734.View ArticlePubMed
- Zielenski J, Corey M, Rozmahel R, Markiewicz D, Aznarez I, Casals T, Larriba S, Mercier B, Cutting GR, Krebsova A, Macek M, Langfelder-Schwind E, Marshall BC, DeCelie-Germana J, Claustres M, Palacio A, Bal J, Nowakowska A, Ferec C, Estivill X, Durie P, Tsui LC: Detection of a cystic fibrosis modifier locus for meconium ileus on human chromosome 19q13. Nat Genet. 1999, 22: 128-129. 10.1038/9635.View ArticlePubMed
- Haston CK, McKerlie C, Newbigging S, Corey M, Rozmahel R, Tsui LC: Detection of modifier loci influencing the lung phenotype of cystic fibrosis knockout mice. Mamm Genome. 2002, 13: 605-613. 10.1007/s00335-002-2190-7.View ArticlePubMed
- Kaur S, Norkina O, Ziemer D, Samuelson LC, De Lisle RC: Acidic duodenal pH alters gene expression in the cystic fibrosis mouse pancreas. Am J Physiol Gastrointest Liver Physiol. 2004, 286: G480-G490. 10.1152/ajpgi.00035.2004.View Article
- Norkina O, Kaur S, Ziemer D, De Lisle RC: Inflammation of the cystic fibrosis mouse small intestine. Am J Physiol Gastrointest Liver Physiol. 2004, 286: G1032-G1041. 10.1152/ajpgi.00473.2003.View ArticlePubMed
- Pemberton AD, Brown JK, Wright SH, Knight PA, McPhee ML, McEuen AR, Forse PA, Miller HR: Purification and characterization of mouse mast cell proteinase-2 and the differential expression and release of mouse mast cell proteinase-1 and -2 in vivo. Clin Exp Allergy. 2003, 33: 1005-1012. 10.1046/j.1365-2222.2003.01720.x.View ArticlePubMed
- O'Donnell LC, Druhan LJ, Avalos BR: Molecular characterization and expression analysis of leucine-rich alpha2-glycoprotein, a novel marker of granulocytic differentiation. J Leukoc Biol. 2002, 72: 478-485.PubMed
- Saito K, Tanaka T, Kanda H, Ebisuno Y, Izawa D, Kawamoto S, Okubo K, Miyasaka M: Gene expression profiling of mucosal addressin cell adhesion molecule- 1+ high endothelial venule cells (HEV) and identification of a leucine- rich HEV glycoprotein as a HEV marker. J Immunol. 2002, 168: 1050-1059.View ArticlePubMed
- Bistrup A, Tsay D, Shenoy P, Singer MS, Bangia N, Luther SA, Cyster JG, Ruddle NH, Rosen SD: Detection of a sulfotransferase (HEC-GlcNAc6ST) in high endothelial venules of lymph nodes and in high endothelial venule-like vessels within ectopic lymphoid aggregates: relationship to the MECA-79 epitope. Am J Pathol. 2004, 164: 1635-1644.PubMed CentralView ArticlePubMed
- Kobayashi M, Mitoma J, Nakamura N, Katsuyama T, Nakayama J, Fukuda M: Induction of peripheral lymph node addressin in human gastric mucosa infected by Helicobacter pylori. Proc Natl Acad Sci U S A. 2004, 101: 17807-17812. 10.1073/pnas.0407503101.PubMed CentralView ArticlePubMed
- Xue H, O'Neill D, Morrow J, Bank A: A novel mouse gene, HemT, encoding an hematopoietic cell-specific transcript. Gene. 1999, 231: 49-58. 10.1016/S0378-1119(99)00099-2.View ArticlePubMed
- Urieli-Shoval S, Linke RP, Matzner Y: Expression and function of serum amyloid A, a major acute-phase protein, in normal and disease states. Curr Opin Hematol. 2000, 7: 64-69. 10.1097/00062752-200001000-00012.View ArticlePubMed
- Suzuki A, Hanada T, Mitsuyama K, Yoshida T, Kamizono S, Hoshino T, Kubo M, Yamashita A, Okabe M, Takeda K, Akira S, Matsumoto S, Toyonaga A, Sata M, Yoshimura A: CIS3/SOCS3/SSI3 plays a negative regulatory role in STAT3 activation and intestinal inflammation. J Exp Med. 2001, 193: 471-481. 10.1084/jem.193.4.471.PubMed CentralView ArticlePubMed
- Mollenhauer J, Wiemann S, Scheurlen W, Korn B, Hayashi Y, Wilgenbus KK, von Deimling A, Poustka A: DMBT1, a new member of the SRCR superfamily, on chromosome 10q25.3-26.1 is deleted in malignant brain tumours. Nature Genet. 1997, 17: 32-39. 10.1038/ng0997-32.View ArticlePubMed
- Sun FS, Kaur S, Ziemer D, Banerjee S, Samuelson LC, De Lisle RC: Decreased gastric bacterial killing and upregulation of protective genes in the small intestine in the gastrin deficient mouse. Dig Dis Sci. 2003, 48: 976-985. 10.1023/A:1023068116934.View ArticlePubMed
- Snouwaert JN, Brigman KK, Latour AM, Malouf NN, Boucher RC, Smithies O, Koller BH: An animal model for cystic fibrosis made by gene targeting. Science. 1992, 257: 1083-1088.View ArticlePubMed
- Parmley RR, Gendler SJ: Cystic fibrosis mice lacking muc1 have reduced amounts of intestinal mucus. J Clin Invest. 1998, 102: 1798-1806.PubMed CentralView ArticlePubMed
- Grubb BR, Gabriel SE: Intestinal physiology and pathology in gene-targeted mouse models of cystic fibrosis. Am J Physiol. 1997, 273: G258-G266.PubMed
- Clarke LL, Gawenis LR, Franklin CL, Harline MC: Increased survival of CFTR knockout mice with an oral osmotic laxative. Lab Anim Sci. 1996, 46: 612-618.PubMed
- Kelley KA, Stamm S, Kozak CA: Expression and chromosome localization of the murine cystic fibrosis transmembrane conductance regulator. Genomics. 1992, 13: 381-388. 10.1016/0888-7543(92)90257-S.View ArticlePubMed
- Obermeier F, Schwarz H, Dunger N, Strauch UG, Grunwald N, Scholmerich J, Falk W: OX40/OX40L interaction induces the expression of CXCR5 and contributes to chronic colitis induced by dextran sulfate sodium in mice. Eur J Immunol. 2003, 33: 3265-3274. 10.1002/eji.200324124.View ArticlePubMed
- Ji HB, Liao G, Faubion WA, Abadia-Molina AC, Cozzo C, Laroux FS, Caton A, Terhorst C: Cutting edge: the natural ligand for glucocorticoid-induced TNF receptor-related protein abrogates regulatory T cell suppression. J Immunol. 2004, 172: 5823-5827.View ArticlePubMed
- Smith ML, Olson TS, Ley K: CXCR2- and E-selectin-induced neutrophil arrest during inflammation in vivo. J Exp Med. 2004, 200: 935-939. 10.1084/jem.20040424.PubMed CentralView ArticlePubMed
- Fraser CC, Howie D, Morra M, Qiu Y, Murphy C, Shen Q, Gutierrez-Ramos JC, Coyle A, Kingsbury GA, Terhorst C: Identification and characterization of SF2000 and SF2001, two new members of the immune receptor SLAM/CD2 family. Immunogenetics. 2002, 53: 843-850. 10.1007/s00251-001-0415-7.View ArticlePubMed
- Rumsaeng V, Vliagoftis H, Oh CK, Metcalfe DD: Lymphotactin gene expression in mast cells following Fc(epsilon) receptor I aggregation: modulation by TGF-beta, IL-4, dexamethasone, and cyclosporin A. J Immunol. 1997, 158: 1353-1360.PubMed
- Li CK, Pender SL, Pickard KM, Chance V, Holloway JA, Huett A, Goncalves NS, Mudgett JS, Dougan G, Frankel G, MacDonald TT: Impaired immunity to intestinal bacterial infection in stromelysin-1 (matrix metalloproteinase-3)-deficient mice. J Immunol. 2004, 173: 5171-5179.View ArticlePubMed
- Ayabe T, Satchell DP, Pesendorfer P, Tanabe H, Wilson CL, Hagen SJ, Ouellette AJ: Activation of Paneth cell alpha-defensins in mouse small intestine. J Biol Chem. 2002, 277: 5219-5228. 10.1074/jbc.M109410200.View ArticlePubMed
- McCafferty DM, Smith CW, Granger DN, Kubes P: Intestinal inflammation in adhesion molecule-deficient mice: an assessment of P-selectin alone and in combination with ICAM-1 or E-selectin. J Leukoc Biol. 1999, 66: 67-74.PubMed
- Galli SJ, Tsai M, Gordon JR, Geissler EN, Wershil BK: Analyzing mast cell development and function using mice carrying mutations at W/c-kit or Sl/MGF (SCF) loci. Ann N Y Acad Sci. 1992, 664: 69-88.View ArticlePubMed
- Puel A, Mevel JC, Bouthillier Y, Feingold N, Fridman WH, Mouton D: Toward genetic dissection of high and low antibody responsiveness in Biozzi mice. Proc Natl Acad Sci U S A. 1996, 93: 14742-14746. 10.1073/pnas.93.25.14742.PubMed CentralView ArticlePubMed
- Ouellette AJ: Paneth cells and innate immunity in the crypt microenvironment. Gastroenterology. 1997, 113: 1779-1784.View ArticlePubMed
- Zheng S, Xu W, Bose S, Banerjee AK, Haque SJ, Erzurum SC: Impaired nitric oxide synthase-2 signaling pathway in cystic fibrosis airway epithelium. Am J Physiol Lung Cell Mol Physiol. 2004, 287: L374-L381. 10.1152/ajplung.00039.2004.View ArticlePubMed
- Dumoutier L, Louahed J, Renauld JC: Cloning and characterization of IL-10-related T cell-derived inducible factor (IL-TIF), a novel cytokine structurally related to IL-10 and inducible by IL-9. J Immunol. 2000, 164: 1814-1819.View ArticlePubMed
- Pfitzner E, Kliem S, Baus D, Litterst CM: The role of STATs in inflammation and inflammatory diseases. Curr Pharm Des. 2004, 10: 2839-2850. 10.2174/1381612043383638.View ArticlePubMed
- Friis-Hansen L, Sundler F, Li Y, Gillespie PJ, Saunders TL, Greenson JK, Owyang C, Rehfeld JF, Samuelson LC: Impaired gastric acid secretion in gastrin-deficient mice. Am J Physiol. 1998, 274: G561-G568.PubMed
- Eckman EA, Cotton CU, Kube DM, Davis PB: Dietary changes improve survival of CFTR S489X homozygous mutant mouse. Am J Physiol. 1995, 269: L625-L630.PubMed
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.