Vitamin D and the vitamin D receptor are critical for control of the innate immune response to colonic injury
© Froicu and Cantorna; licensee BioMed Central Ltd. 2007
Received: 29 September 2006
Accepted: 30 March 2007
Published: 30 March 2007
The active form of vitamin D (1,25(OH)2D3) has been shown to inhibit development of inflammatory bowel disease (IBD) in IL-10 KO mice. Here, the role of the vitamin D receptor (VDR) and 1,25(OH)2D3 in acute experimental IBD was probed.
VDR KO mice were extremely sensitive to dextran sodium sulfate (DSS) and there was increased mortality of the VDR KO mice at doses of DSS that only caused a mild form of colitis in wildtype (WT) mice. DSS colitis in the VDR KO mice was accompanied by high colonic expression of TNF-α, IL-1 α, IL-1β, IL-12, IFN-γ, IL-10, MIP-1α and KC. DSS concentrations as low as 0.5% were enough to induce bleeding, ulceration and weight loss in VDR KO mice. VDR KO mice failed to recover following the removal of DSS, while WT mice showed signs of recovery within 5 days of DSS removal. The early mortality of DSS treated VDR KO mice was likely due to perforation of the bowel and resulting endotoxemia. VDR KO mice were hyper-responsive to exogenously injected LPS and cultures of the peritoneal exudates of moribund DSS treated VDR KO mice were positive for bacterial growth. 1,25(OH)2D3 in the diet or rectally decreased the severity and extent of DSS-induced inflammation in WT mice.
The data point to a critical role for the VDR and 1,25(OH)2D3 in control of innate immunity and the response of the colon to chemical injury.
The two forms of inflammatory bowel disease (IBD): Crohn's disease and ulcerative colitis are chronic diseases characterized by aberrant responses to luminal bacteria in genetically susceptible subjects . Although IBD are chronic diseases, the initiation of the inflammation and reactivations of the disease are associated with engagement of the innate immune response and progressive induction of IL-12, IL-1β, and TNF-α in the intestine .
The vitamin D receptor (VDR) is a ligand inducible transcription factor that has been shown to be an important regulator of many experimental autoimmune diseases including IBD . A major source of vitamin D results from its manufacture via a photolysis reaction in the skin. Dietary intake of vitamin D is problematic since there are few foods, which are naturally rich in vitamin D. There is mounting evidence for a link between vitamin D availability either from sunshine or diet and the prevalence of IBD . In addition, vitamin D deficiency is common in patients with IBD . Vitamin D is biologically inactive and two hydroxylation reactions occurring in the liver and kidney result in production of active vitamin D (1,25(OH)2D3). 1,25(OH)2D3is the form of vitamin D that binds to the VDR and inhibits experimental autoimmunity.
Vitamin D deficiency and VDR deficiency have been shown to exacerbate chronic IBD in IL-10 KO mice [5, 6]. Furthermore, treatment of IL-10 KO mice with 1,25(OH)2D3 resulted in the suppression of IBD symptoms . The effects of vitamin D and 1,25(OH)2D3 in IBD have begun to be explored and include direct effects of vitamin D on T cells and innate immune cells. Suppression of TNF-α is one mechanism underlying the efficacy of 1,25(OH)2D3 in vivo . In the gut it is likely that the targets of vitamin D will include epithelial cells, innate as well as acquired immune cells.
Macrophage are important vitamin D targets since they are a potential source of the 1 alpha hydroxylase enzyme (Cyp27B1) that converts the provitamin D hormone 25(OH)D3 to active VDR binding 1,25(OH)2D3 . Macrophage expression of Cyp27B1 has been shown to be increased following TLR ligation in vitro . Macrophage and the TLR pathways are critical regulators of experimental IBD. The TLR-4, TLR-2 and MyD88 KO mice are extremely susceptible to dextran sodium sulfate (DSS) induced colitis . Little is known on whether vitamin D regulates these pathways to maintain gastrointestinal homeostasis in vivo.
DSS initiates mucosal epithelial cell damage by disrupting barrier function, leading to ulceration, and bleeding . A relatively slow mucosal repair process occurs following withdrawal of DSS in wildtype (WT) mice . DSS induced colitis results due to stimulation of the innate immune response since T and B cell-deficient animals such as SCID mice , and also SCID mice depleted of NK cells develop DSS colitis . The model is characterized by macrophage production of IL-1β, IL-6, and TNF-α . Macrophage induction at mucosal surfaces are early triggers in an inflammatory cascade that leads to destruction of the intestinal wall.
The role of the VDR and 1,25(OH)2D3 in regulation of the early innate immune response to DSS was probed in mice. Expression of the VDR was found to be critical to control the innate immune response in the gut. In addition, VDR KO mice had a delayed recovery following DSS withdrawal. 1,25(OH)2D3 treatments were protective and controlled the early innate response in the colon. VDR KO mice were extremely susceptible to the TLR-4 ligand LPS and furthermore the early death of the VDR KO mice following DSS challenge was associated with bacterial recovery from the peritoneal cavity.
Acute DSS colitis is fatal in VDR KO mice
Delayed recovery of the VDR KO mice following removal of DSS
In this acute colitis model there is a recovery phase that follows the cessation of DSS . WT mice recovered body weight (Fig. 1B) and the colon lengthened (Fig. 1C) within 5 days of DSS removal as expected. The recovery phase was delayed in surviving VDR KO mice when compared to WT mice as evident by the ultimate inability of VDR KO mice to completely regain BW even 30 days after treatment was stopped (Fig. 1B). Conversely, by day 10 post DSS the WT colons had recovered completely (Fig. 1C) while the VDR KO colons were still significantly shortened and not different than 5 days post DSS (Fig. 1C). Even at lower doses of DSS (1.5%) the recovery period for VDR KO mice was 33 +/- 3.5 days while for WT mice weight was completely regained by 12+/- 1.5 days.
VDR KO mice are sensitive to very low doses of DSS
Very low doses of (0.5%–2%) DSS that produce little to no harm to the WT intestinal mucosa were tested in VDR KO mice. In VDR KO mice, a dose of 0.5%–1% DSS induced a loss of approximately 15%–18% of the initial BW while this dose of DSS did not affect the BW of WT mice (Fig 1D). A dose of 0.5% DSS in VDR KO mice induced the same decrease in BW as 2.5% DSS in the WT mice (Fig. 1D).
Hematological and histological alterations in DSS-treated VDR KO mice
Over-expression of many cytokines in the colon of VDR KO mice treated with DSS
Chemokines recruit neutrophils, macrophage and other effector immune cells to the site of injury. While, the colons of WT and VDR KO mice produced undetectable levels of KC-1, and MIP-1 prior to DSS administration (data not shown); KC-1 and MIP-1 were detectable 5 days after the administration of DSS (Fig. 5) in the colon of both the VDR KO and WT mice. MIP-1 was significantly higher at 5 and 10 days post DSS treatment in VDR KO mice compared to WT mice (Fig. 5). KC production was increased to a similar level in colonic extracts from VDR KO and WT mice 5 days after DSS treatment (Fig. 5) and then decreased in both mouse types by day 10. However, at day 10 VDR KO mice had significantly higher levels of KC in the colon compared to WT mice (Fig. 5).
Lethal endotoxemia in VDR KO mice
1,25 (OH)2D3 improves symptoms of DSS colitis in WT mice
Absence of the VDR results in mice that are extremely susceptible to chemical injury in the gut. DSS treated VDR KO mice are anemic, have high white blood cell counts, large amounts of blood in the colon, and many inflammatory cytokines expressed at high levels. A breach in the intestinal mucosa would lead to the entry of bacteria into the blood stream followed by an excessive, uncontrolled, systemic inflammation including, at the extreme, septic shock. Masubuchi et. al have shown that endotoxin levels detected in the portal blood of rats treated with DSS were higher than those in control rats . In humans, systemic endotoxemia has been described in ulcerative colitis [16, 17] and Crohn's disease patients and shown to correlate positively with disease activity, pro-inflammatory cytokine production and the extent of intestinal ulceration [18–23]. VDR deficient mice are extremely sensitive to intravenous or intraperitoneal administration of LPS, supporting the possibility that VDR KO mice with colitis die due to endotoxemia. In addition, bacteria was cultured from the peritoneal cavities of moribund VDR KO mice following DSS treatment. All of the data support the hypothesis that the early mortality of the VDR KO mice treated with DSS is due to perforation of the gut and resulting endotoxemia.
DSS induced colitis is a chemical that damages the colonic epithelium  with subsequent recruitment and activation of inflammatory cells and upregulation of inflammatory mediators . During injury or inflammation, intestinal epithelial cells are rapidly proliferating and this process of mucosal repair and regeneration is critical for gut homeostasis . The VDR is highly expressed in human  and mouse  colonic mucosa and intestinal epithelial cells . 1,25(OH)2D3 has been shown to control normal villus and crypt development by regulating proliferation and differentiation of intestinal cells . Furthermore, 1,25(OH)2D3 is an important regulator of cell growth and differentiation in many tissues including the colon . In DSS colitis most of the pathological changes are localized to the distal colon which is a site of low proliferation of epithelial cells . Others have shown that the baseline proliferative state of colonic eptithelial cells in the crypts of VDR KO mice are elevated and showed increased expression of markers for cycling cells (proliferating cell nuclear antigen and cyclin D1) when compared to WTs . Although increased proliferation in the colon of VDR KO mice might be seen as beneficial, it has been shown that crypts with increased numbers of epithelial cells in cell cycle are more susceptible to radiation-induced injury as determined by their inability to repopulate the crypt . The effectiveness of 1,25(OH)2D3 in protecting the colon and the heightened susceptibility of the VDR KO gut to DSS colitis is likely due in part to the importance of vitamin D and VDR signaling in control of epithelial growth and proliferation.
Once the mucosal barrier is breached, the submucosa is exposed to a vast pool of luminal antigens, including foods and bacteria, and the innate immune responses are engaged to produce large amounts of cytokines. Analysis of cytokine production by colonic homogenates revealed significant elevation of TNF-α, IL-1α, IL-1β, IL-12p70, IFN-γ and IL-10 in VDR KO mice treated with DSS when compared with WT mice. Human and animal studies support the idea that TNF-α and IFN-γ are important pathological mediators of IBD . In humans with IBD approximately two thirds of the patients responded to anti-TNF-α treatments , and in mice the intestinal inflammation was significantly attenuated by anti-IFN-γ and/or anti-TNF-α monoclonal antibodies . The production of IFN-γ, TNF-α, IL-1α and IL-1β in the colonic homogenates of VDR KO mice was substantially higher at 10 days post-DSS than in WT mice consistent with the observed delay in recovery from inflammation in these mice. The prolonged expression of inflammatory cytokines corresponded with the increased susceptibility and delayed recovery of the VDR KO mice.
During experimental colitis members of the α-chemokine family are involved in the recruitment of immune cells and the development of intestinal inflammation. Ajuebor et. al have shown in experimental IBD that colonic KC and MIP-1α expression led to leukocyte recruitment in the gut . Furthermore studies by Banks et. al showed that the expression of MIP-1α correlated with the severity of colonic inflammation in patients with IBD . The increased levels of KC and MIP-1α in the colons of VDR KO suggest that in the absence of the VDR many more inflammatory cells may be recruited to the site of injury and then produce inflammatory cytokines that result in severe and fatal form of colitis.
1,25(OH)2D3 treatments both in the food or locally reduced colitis symptoms in WT mice. 1,25(OH)2D3 treated WT mice had increased IL-10 production that might serve to inhibit other cytokine responses and lead to a dampening of the cytokine storm in the colon. Furthermore 1,25(OH)2D3 has the ability to directly induce antimicrobial gene expression and activity of antimicrobial peptide CAMP and defensin β2 genes . CAMP is a potent antisepsis agent that blocks macrophage induction, enhances the survival of mice treated with lethal doses of LPS  and accelerates epithelial wound healing . The induction of CAMP and other antimicrobial genes suggested that 1,25(OH)2D3 might be protective against sepsis after injury and might accelerate epithelial wound healing .
A model develops where the 1,25(OH)2D3 that is either produced or administered locally in the colon increases epithelial cell resistance to injury and suppresses innate immune responses to luminal antigens through VDR signaling. In the absence of the VDR inflammation in the gut is amplified, colonic epithelial cell proliferation is unregulated and the host fails to adequately maintain gastrointestinal integrity following chemical insult. The data identify vitamin D as a key regulator of gastrointestinal homeostasis and an important player in regulation of the innate immune response.
Weight (20–25 g) and sex matched 10–12 week old C57BL/6 WT and VDR KO (C57BL/6, gift from M. Demay, Harvard University, Cambridge, MA) were bred for use at the Pennsylvania State University (University Park, PA). All procedures were reviewed and approved by the Pennsylvania State University Institutional Animal Care and Use Committee.
Induction of colitis
Mice were administered 0.5%–3.5% DSS (MW = 40 kDa; ICN Biomedicals, Aurora, OH) dissolved in filter-purified and sterilized water ad libitum for 5 days, after which the mice were resumed on water for the remainder of the experiment. Animals were weighed daily and monitored clinically for rectal bleeding, diarrhea, and general signs of morbidity. Moribund mice or mice that had lost more than 25% of their body weight were sacrificed and listed as dead following induction of DSS colitis.
The gross colonic blood scoring system previously described by Siegmund et al was used. The colonic bleeding score was as follows: 0- no visible blood in the entire colon, 1-blood detected in less than 1/3 of the colon, 2- blood detected in less than 2/3 of the colon, 3- blood visible throughout the entire colon. The entire colon from cecum to anus was removed and the length was measured and reported as colonic length as described .
The distal colon were removed from the mice, fixed in 10% formalin and sent to the Pennslyvania State University Animal Diagnostic Laboratories (University Park, PA) for H&E staining. Histological analysis was performed blinded by 2 independent investigators on a scale from 0 to 40 as follows: severity of inflammation (0–3: none, slight, moderate, severe), extent of injury (0–3: none, mucosal, mucosal and submucosal, transmural), and crypt damage (0–4: none, basal 1/3 damaged, basal 2/3 damaged, only surface epithelium intact, entire crypt and epithelium lost). Each score was then multiplied by a factor equivalent with the percentage of tissue involvement (× 1: 0–25%, × 2: 26–50%, × 3: 51–75%, × 4: 76–100%).
Peripheral blood analysis
Blood was collected by cardiac puncture in tubes coated with EDTA (Becton Dickinson Vacutainer System, NJ) and analyzed using an ADVIA 120 Hematology System (Bayer Diagnostic, NY). For some experiments 100–200 μl of blood was collected by retroorbital sinus bleeding using heparinized microcapillary pipettes.
The distal colon was weighed and the same amount of tissue was cut open and washed in 1XPBS containing penicillin (100 U/ml) and streptomycin (100 μg/ml). Tissue was then homogenized in 1 ml PBS using a razor blade. The homogenized colon tissue was centrifuged at 10,000 g at 4°C for 10 min. Cytokine concentrations were determined in the supernatant.
Cytokine and chemokine ELISA
Serum and supernatants were assayed for mouse TNF-α, IL-12p70, IFN-γ, IL-1α, IL-1β, IL-10 production using Ab pairs and standards provided in the BD Pharmingen kits ELISA (San Diego, CA) according to the manufacturer's instructions. For KC and MIP-1α the ELISA kits were from R&D Systems. (Minneapolis, MN). The limits of detection were 31 pg/ml TNF-α, 125 pg/ml IL-12 p70,125 pg/ml IFN-γ, 31 pg/ml IL-1α, 31 pg/ml IL-1β, 31 pg/ml IL-10, 16 pg/ml KC and 31 pg/ml MIP-1α.
C57BL/6 mice were injected iv or ip with LPS from Escherichia coli 0111:B4 (Sigma, St Louis, MO) at a dose of 10 mg/kg body weight. Mice were monitored 3–4 times daily during endotoxic shock, and moribund animals were sacrificed.
Mice received 50 ng/daily of 1,25(OH)2D3 in the diet as described  elsewhere 1 week prior and throughout DSS administration. For local treatment, 50 ng of 1,25(OH)2D3 was dissolved in 20 uL corn oil and administered rectally 1 day prior to DSS administration and every other day thereafter for the duration of the experiment. Control mice received the corresponding amount of ethanol diluted in corn oil.
Statistical analysis was performed using the paired Student's t test and ANOVAs (StatView; SAS Institute, Cary, NC). P values < 0.05 were considered significant. Error bars represent +/- SEM. The log-rank test was used to compare Kaplan-Meier survival curves.
- DSS :
dextran sodium sulfate
inflammatory bowel disease
vitamin D receptor
This work was supported by the Crohn's and Colitis Foundation of America, Predoctoral Research Award (to MF) and National Institutes of Health-National Institute of Neurological Disorders and Stroke Grant 1R01 NS38888 (to MTC).
- Bouma G, Strober W: The immunological and genetic basis of inflammatory bowel disease. Nat Rev Immunol. 2003, 3 (7): 521-533. 10.1038/nri1132.View ArticlePubMedGoogle Scholar
- Egger B, Bajaj-Elliott M, MacDonald TT, Inglin R, Eysselein VE, Buchler MW: Characterisation of acute murine dextran sodium sulphate colitis: cytokine profile and dose dependency. Digestion. 2000, 62 (4): 240-248. 10.1159/000007822.View ArticlePubMedGoogle Scholar
- Cantorna MT, Mahon BD: Mounting evidence for vitamin D as an environmental factor affecting autoimmune disease prevalence. Exp Biol Med (Maywood). 2004, 229 (11): 1136-1142.Google Scholar
- Cantorna MT: Vitamin D and autoimmunity: is vitamin D status an environmental factor affecting autoimmune disease prevalence?. Proc Soc Exp Biol Med. 2000, 223 (3): 230-233. 10.1046/j.1525-1373.2000.22333.x.View ArticlePubMedGoogle Scholar
- Cantorna MT, Munsick C, Bemiss C, Mahon BD: 1,25-Dihydroxycholecalciferol prevents and ameliorates symptoms of experimental murine inflammatory bowel disease. J Nutr. 2000, 130 (11): 2648-2652.PubMedGoogle Scholar
- Froicu M, Weaver V, Wynn TA, McDowell MA, Welsh JE, Cantorna MT: A crucial role for the vitamin D receptor in experimental inflammatory bowel diseases. Mol Endocrinol. 2003, 17 (12): 2386-2392. 10.1210/me.2003-0281.View ArticlePubMedGoogle Scholar
- Zhu Y, Mahon BD, Froicu M, Cantorna MT: Calcium and 1alpha,25-dihydroxyvitamin D3 target the TNF-alpha pathway to suppress experimental inflammatory bowel disease. Eur J Immunol. 2005, 35 (1): 217-224. 10.1002/eji.200425491.View ArticlePubMedGoogle Scholar
- Zehnder D, Bland R, Chana RS, Wheeler DC, Howie AJ, Williams MC, Stewart PM, Hewison M: Synthesis of 1,25-dihydroxyvitamin D(3) by human endothelial cells is regulated by inflammatory cytokines: a novel autocrine determinant of vascular cell adhesion. J Am Soc Nephrol. 2002, 13 (3): 621-629.PubMedGoogle Scholar
- Liu PT, Stenger S, Li H, Wenzel L, Tan BH, Krutzik SR, Ochoa MT, Schauber J, Wu K, Meinken C, Kamen DL, Wagner M, Bals R, Steinmeyer A, Zugel U, Gallo RL, Eisenberg D, Hewison M, Hollis BW, Adams JS, Bloom BR, Modlin RL: Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response. Science. 2006, 311 (5768): 1770-1773. 10.1126/science.1123933.View ArticlePubMedGoogle Scholar
- Rakoff-Nahoum S, Paglino J, Eslami-Varzaneh F, Edberg S, Medzhitov R: Recognition of commensal microflora by toll-like receptors is required for intestinal homeostasis. Cell. 2004, 118 (2): 229-241. 10.1016/j.cell.2004.07.002.View ArticlePubMedGoogle Scholar
- Okayasu I, Hatakeyama S, Yamada M, Ohkusa T, Inagaki Y, Nakaya R: A novel method in the induction of reliable experimental acute and chronic ulcerative colitis in mice. Gastroenterology. 1990, 98 (3): 694-702.PubMedGoogle Scholar
- Axelsson LG, Landstrom E, Goldschmidt TJ, Gronberg A, Bylund-Fellenius AC: Dextran sulfate sodium (DSS) induced experimental colitis in immunodeficient mice: effects in CD4(+) -cell depleted, athymic and NK-cell depleted SCID mice. Inflamm Res. 1996, 45 (4): 181-191. 10.1007/BF02285159.View ArticlePubMedGoogle Scholar
- Dieleman LA, Ridwan BU, Tennyson GS, Beagley KW, Bucy RP, Elson CO: Dextran sulfate sodium-induced colitis occurs in severe combined immunodeficient mice. Gastroenterology. 1994, 107 (6): 1643-1652.PubMedGoogle Scholar
- Williams KL, Fuller CR, Dieleman LA, DaCosta CM, Haldeman KM, Sartor RB, Lund PK: Enhanced survival and mucosal repair after dextran sodium sulfate-induced colitis in transgenic mice that overexpress growth hormone. Gastroenterology. 2001, 120 (4): 925-937. 10.1053/gast.2001.22470.View ArticlePubMedGoogle Scholar
- Masubuchi Y, Horie T: Endotoxin-mediated disturbance of hepatic cytochrome P450 function and development of endotoxin tolerance in the rat model of dextran sulfate sodium-induced experimental colitis. Drug Metab Dispos. 2004, 32 (4): 437-441. 10.1124/dmd.32.4.437.View ArticlePubMedGoogle Scholar
- Palmer KR, Duerden BI, Holdsworth CD: Bacteriological and endotoxin studies in cases of ulcerative colitis submitted to surgery. Gut. 1980, 21 (10): 851-854.PubMed CentralView ArticlePubMedGoogle Scholar
- Amati L, Caradonna L, Leandro G, Magrone T, Minenna M, Faleo G, Pellegrino NM, Jirillo E, Caccavo D: Immune abnormalities and endotoxemia in patients with ulcerative colitis and in their first degree relatives: attempts at neutralizing endotoxin-mediated effects. Curr Pharm Des. 2003, 9 (24): 1937-1945. 10.2174/1381612033454324.View ArticlePubMedGoogle Scholar
- Gardiner KR, Anderson NH, McCaigue MD, Erwin PJ, Halliday MI, Rowlands BJ: Enteral and parenteral anti-endotoxin treatment in experimental colitis. Hepatogastroenterology. 1994, 41 (6): 554-558.PubMedGoogle Scholar
- Aoki K: A study of endotoxemia in ulcerative colitis and Crohn's disease. I. Clinical study. Acta Med Okayama. 1978, 32 (2): 147-158.PubMedGoogle Scholar
- Aoki K: A study of endotoxemia in ulcerative colitis and Crohn's disease. II. Experimental study. Acta Med Okayama. 1978, 32 (3): 207-216.PubMedGoogle Scholar
- Jacob AI, Goldberg PK, Bloom N, Degenshein GA, Kozinn PJ: Endotoxin and bacteria in portal blood. Gastroenterology. 1977, 72 (6): 1268-1270.PubMedGoogle Scholar
- Gardiner KR, Halliday MI, Barclay GR, Milne L, Brown D, Stephens S, Maxwell RJ, Rowlands BJ: Significance of systemic endotoxaemia in inflammatory bowel disease. Gut. 1995, 36 (6): 897-901.PubMed CentralView ArticlePubMedGoogle Scholar
- Caradonna L, Amati L, Magrone T, Pellegrino NM, Jirillo E, Caccavo D: Enteric bacteria, lipopolysaccharides and related cytokines in inflammatory bowel disease: biological and clinical significance. J Endotoxin Res. 2000, 6 (3): 205-214. 10.1179/096805100101532063.PubMedGoogle Scholar
- Kitajima S, Takuma S, Morimoto M: Tissue distribution of dextran sulfate sodium (DSS) in the acute phase of murine DSS-induced colitis. J Vet Med Sci. 1999, 61 (1): 67-70. 10.1292/jvms.61.67.View ArticlePubMedGoogle Scholar
- Dieleman LA, Palmen MJ, Akol H, Bloemena E, Pena AS, Meuwissen SG, Van Rees EP: Chronic experimental colitis induced by dextran sulphate sodium (DSS) is characterized by Th1 and Th2 cytokines. Clin Exp Immunol. 1998, 114 (3): 385-391. 10.1046/j.1365-2249.1998.00728.x.PubMed CentralView ArticlePubMedGoogle Scholar
- Kiela PR, Midura AJ, Kuscuoglu N, Jolad SD, Solyom AM, Besselsen DG, Timmermann BN, Ghishan FK: Effects of Boswellia serrata in mouse models of chemically induced colitis. Am J Physiol Gastrointest Liver Physiol. 2005, 288 (4): G798-808. 10.1152/ajpgi.00433.2004.View ArticlePubMedGoogle Scholar
- Cross HS, Bareis P, Hofer H, Bischof MG, Bajna E, Kriwanek S, Bonner E, Peterlik M: 25-Hydroxyvitamin D(3)-1alpha-hydroxylase and vitamin D receptor gene expression in human colonic mucosa is elevated during early cancerogenesis. Steroids. 2001, 66 (3-5): 287-292. 10.1016/S0039-128X(00)00153-7.View ArticlePubMedGoogle Scholar
- Froicu M, Zhu Y, Cantorna MT: Vitamin D receptor is required to control gastrointestinal immunity in IL-10 knockout mice. Immunology. 2006, 117 (3): 310-318. 10.1111/j.1365-2567.2005.02290.x.PubMed CentralView ArticlePubMedGoogle Scholar
- Zehnder D, Bland R, Williams MC, McNinch RW, Howie AJ, Stewart PM, Hewison M: Extrarenal expression of 25-hydroxyvitamin d(3)-1 alpha-hydroxylase. J Clin Endocrinol Metab. 2001, 86 (2): 888-894. 10.1210/jc.86.2.888.PubMedGoogle Scholar
- Suda T, Shinki T, Takahashi N: The role of vitamin D in bone and intestinal cell differentiation. Annu Rev Nutr. 1990, 10: 195-211. 10.1146/annurev.nu.10.070190.001211.View ArticlePubMedGoogle Scholar
- Kallay E, Pietschmann P, Toyokuni S, Bajna E, Hahn P, Mazzucco K, Bieglmayer C, Kato S, Cross HS: Characterization of a vitamin D receptor knockout mouse as a model of colorectal hyperproliferation and DNA damage. Carcinogenesis. 2001, 22 (9): 1429-1435. 10.1093/carcin/22.9.1429.View ArticlePubMedGoogle Scholar
- Booth D, Potten CS: Protection against mucosal injury by growth factors and cytokines. J Natl Cancer Inst Monogr. 2001, 16-20.Google Scholar
- Papadakis KA, Targan SR: Role of cytokines in the pathogenesis of inflammatory bowel disease. Annu Rev Med. 2000, 51: 289-298. 10.1146/annurev.med.51.1.289.View ArticlePubMedGoogle Scholar
- Targan SR, Hanauer SB, van Deventer SJ, Mayer L, Present DH, Braakman T, DeWoody KL, Schaible TF, Rutgeerts PJ: A short-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor alpha for Crohn's disease. Crohn's Disease cA2 Study Group. N Engl J Med. 1997, 337 (15): 1029-1035. 10.1056/NEJM199710093371502.View ArticlePubMedGoogle Scholar
- Obermeier F, Kojouharoff G, Hans W, Scholmerich J, Gross V, Falk W: Interferon-gamma (IFN-gamma)- and tumour necrosis factor (TNF)-induced nitric oxide as toxic effector molecule in chronic dextran sulphate sodium (DSS)-induced colitis in mice. Clin Exp Immunol. 1999, 116 (2): 238-245. 10.1046/j.1365-2249.1999.00878.x.PubMed CentralView ArticlePubMedGoogle Scholar
- Ajuebor MN, Swain MG: Role of chemokines and chemokine receptors in the gastrointestinal tract. Immunology. 2002, 105 (2): 137-143. 10.1046/j.1365-2567.2002.01309.x.PubMed CentralView ArticlePubMedGoogle Scholar
- Banks C, Bateman A, Payne R, Johnson P, Sheron N: Chemokine expression in IBD. Mucosal chemokine expression is unselectively increased in both ulcerative colitis and Crohn's disease. J Pathol. 2003, 199 (1): 28-35. 10.1002/path.1245.View ArticlePubMedGoogle Scholar
- Wang TT, Nestel FP, Bourdeau V, Nagai Y, Wang Q, Liao J, Tavera-Mendoza L, Lin R, Hanrahan JW, Mader S, White JH: Cutting edge: 1,25-dihydroxyvitamin D3 is a direct inducer of antimicrobial peptide gene expression. J Immunol. 2004, 173 (5): 2909-2912.View ArticlePubMedGoogle Scholar
- Scott MG, Davidson DJ, Gold MR, Bowdish D, Hancock RE: The human antimicrobial peptide LL-37 is a multifunctional modulator of innate immune responses. J Immunol. 2002, 169 (7): 3883-3891.View ArticlePubMedGoogle Scholar
- Heilborn JD, Nilsson MF, Kratz G, Weber G, Sorensen O, Borregaard N, Stahle-Backdahl M: The cathelicidin anti-microbial peptide LL-37 is involved in re-epithelialization of human skin wounds and is lacking in chronic ulcer epithelium. J Invest Dermatol. 2003, 120 (3): 379-389. 10.1046/j.1523-1747.2003.12069.x.View ArticlePubMedGoogle Scholar
- Siegmund B, Lehr HA, Fantuzzi G, Dinarello CA: IL-1 beta -converting enzyme (caspase-1) in intestinal inflammation. Proc Natl Acad Sci U S A. 2001, 98 (23): 13249-13254. 10.1073/pnas.231473998.PubMed CentralView ArticlePubMedGoogle Scholar
- Vowinkel T, Mori M, Krieglstein CF, Russell J, Saijo F, Bharwani S, Turnage RH, Davidson WS, Tso P, Granger DN, Kalogeris TJ: Apolipoprotein A-IV inhibits experimental colitis. J Clin Invest. 2004, 114 (2): 260-269. 10.1172/JCI200421233.PubMed CentralView ArticlePubMedGoogle Scholar
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