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Cancer Res. 2006 Apr 15;66(8):4516-24.

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Inhibition of p38 by vitamin D reduces interleukin-6 production in normal prostate cells via mitogen-activated protein kinase phosphatase 5: implications for prostate cancer prevention by vitamin D.

Nonn L, Peng L, Feldman D, Peehl DM.

Department of Urology, Stanford University School of Medicine, Stanford, California 94305-5118, USA.

Although numerous studies have implicated vitamin D in preventing prostate cancer, the underlying mechanism(s) remains unclear. Using normal human prostatic epithelial cells, we examined the role of mitogen-activated protein kinase phosphatase 5 (MKP5) in mediating cancer preventive activities of vitamin D. Up-regulation of MKP5 mRNA by 1,25-dihydroxyvitamin-D3 (1,25D) was dependent on the vitamin D receptor. We also identified a putative positive vitamin D response element within the MKP5 promoter that associated with the vitamin D receptor following 1,25D treatment. MKP5 dephosphorylates/inactivates the stress-activated protein kinase p38. Treatment of prostate cells with 1,25D inhibited p38 phosphorylation, and MKP5 small interfering RNA blocked this effect. Activation of p38 and downstream production of interleukin 6 (IL-6) are proinflammatory. Inflammation and IL-6 overexpression have been implicated in the initiation and progression of prostate cancer. 1,25D pretreatment inhibited both UV- and tumor necrosis factor alpha-stimulated IL-6 production in normal cells via p38 inhibition. Consistent with inhibition of p38, 1,25D decreased UV-stimulated IL-6 mRNA stabilization. The ability of 1,25D to up-regulate MKP5 was maintained in primary prostatic adenocarcinoma cells but was absent in metastases-derived prostate cancer cell lines. The inability of 1,25D to regulate MKP5 in the metastasis-derived cancer cells suggests there may be selective pressure to eliminate key tumor suppressor functions of vitamin D during cancer progression. These studies reveal MKP5 as a mediator of p38 inactivation and decreased IL-6 expression by 1,25D in primary prostatic cultures of normal and adenocarcinoma cells, implicating decreased prostatic inflammation as a potential mechanism for prostate cancer prevention by 1,25D.

 

J Immunol. 2006 Mar 15;176(6):3780-7.

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Regulation of IL-1 family cytokines IL-1alpha, IL-1 receptor antagonist, and IL-18 by 1,25-dihydroxyvitamin D3 in primary keratinocytes.

Kong J, Grando SA, Li YC.

Department of Medicine, University of Chicago, 5841 South Maryland Avenue, Chicago, IL 60637, USA.

IL-1 family cytokines are key mediators of inflammatory response. Excessive production of these cytokines by keratinocytes has been implicated in inflammatory and hyperproliferative skin diseases. Given the immunosuppressive role of 1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)) and its clinical application in treatment of psoriasis, we investigated the effect of 1,25(OH)(2)D(3) on the expression of IL-1alpha, intracellular IL-1 receptor antagonist (icIL-1Ra), and IL-18 in mouse primary keratinocytes. Treatment of keratinocytes with 1,25(OH)(2)D(3) increased the expression of IL-1alpha and icIL-1Ra and decreased the expression of IL-18 in dose- and time-dependent manners. The magnitude of icIL-1Ra induction was much greater than that of IL-1alpha so that the ratio of icIL-1Ra to IL-1alpha was markedly increased, leading to repression of IL-1 activity. The regulation of these three cytokines by 1,25(OH)(2)D(3) was mediated by vitamin D receptor (VDR), as 1,25(OH)(2)D(3) had no effect in VDR(-/-) keratinocytes, whereas the effect was restored in cells derived from VDR(-/-) mice expressing human VDR. 1,25(OH)(2)D(3) appeared to use different mechanisms to regulate the biosynthesis of IL-1alpha and icIL-1Ra: it increased IL-1alpha mRNA stability whereas it enhanced icIL-1Ra gene transcription. The basal IL-18 expression and activity were much higher in VDR(-/-) keratinocytes and skin, underscoring the importance of the repressive role of vitamin D in IL-18 production. Similar regulation of these cytokines was also seen in primary human keratinocytes. Collectively, these results suggest that vitamin D modulates cutaneous inflammatory reactions, at least in part, by increasing the IL-1Ra to IL-1alpha ratio and suppressing IL-18 synthesis in keratinocytes.

PMID: 16517748 [PubMed - indexed for MEDLINE]

Am J Physiol Endocrinol Metab. 2006 Feb 28; [Epub ahead of print]

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Increased NF-{kappa}B Activity in Fibroblasts Lacking the Vitamin D Receptor.

Sun J, Kong J, Duan Y, Szeto FL, Liao A, Madara JL, Li YC.

Department of Pathology, University of Chicago, Chicago, IL, USA.

1,25-Dihydroxyvitamin D [1,25(OH)2D3] is known to have anti-inflammatory activity; however, the molecular mechanism remains poorly defined. Here we show that the nuclear vitamin D receptor (VDR) is directly involved in the regulation of NF-kappaB activation, a pathway essential for inflammatory response. In mouse embryonic fibroblasts (MEFs) derived from VDR(-/-) mice, the basal level of IkappaBalpha protein was markedly decreased compared to VDR(+/-) MEFs; however, degradation of IkappaBalpha and its phosphorylation in response to TNFalpha treatment or Salmonella infection were not altered in VDR(-/-) cells, neither were the levels of IKKalpha and IKKbeta proteins. Consistent with IkappaBalpha reduction, p65 accumulation in the nucleus was markedly increased in unstimulated VDR(-/-) cells. In addition, the physical interaction between VDR and p65 was absent in VDR(-/-) MEFs, which may free p65 and increase its activity. Consequently, these alterations combined led to a marked increase in nuclear p65 DNA binding and NF-kappaB transcriptional activity; consistently, induction of IL-6 by TNFalpha or IL-1beta was much more robust in VDR(-/-) than in VDR(+/-) cells, indicating that VDR(-/-) cells are more susceptible to inflammatory stimulation. Therefore, cells lacking VDR appear to be more pro-inflammatory due to the intrinsic high NF-kappaB activity. The reduction of IkappaBalpha in VDR(-/-) MEFs may be partially explained by the lack of VDR-mediated stabilization of IkappaBalpha by 1,25(OH)2D3. This is supported by the observation that IkappaBalpha degradation induced by TNFalpha was inhibited by 1,25(OH)2D3 in VDR(+/-) cells, but not in VDR(-/-) cells. Taken together, these data suggest that VDR plays an inhibitory role in the regulation of NF-kappaB activation.

PMID: 16507601 [PubMed - as supplied by publisher]



PMID: 16618780 [PubMed - in process]

 

: J Hepatol. 2006 May;44(5):856-63. Epub 2006 Feb 21.

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Association between vitamin D receptor, CCR5, TNF-alpha and TNF-beta gene polymorphisms and HBV infection and severity of liver disease.

Suneetha PV, Sarin SK, Goyal A, Kumar GT, Shukla DK, Hissar S.

Department of Gastroenterology, GB Pant Hospital, New Delhi-2, India.

BACKGROUND/AIMS: 1,25-dihydroxyvitamin-D is involved in immunomodulation. Expression of vitamin-D receptors in hepatocytes suggests its role in hepatocellular injury. We studied the association of single nucleotide polymorphisms in genes involved in immunoregulatory functions of vitamin-D with susceptibility, severity and persistence of HBV infection. METHODS: Five polymorphisms in VDR, CCR5, TNF-alpha and TNF-beta were studied in 214 chronic hepatitis B patients and 408 controls. Clinical parameters were compared between mild or severe liver disease patients. RESULTS: The frequency of heterozygosity of CCR5Delta32 was higher in chronic hepatitis B patients than controls (4.2 vs 0.73%, P=0.005). Frequency of VDR Apa1 a/a and TNF-beta A/A was higher in severe compared with mild liver disease based on HAI (19.3 vs 5.4%, P=0.003 and 18.1 vs 3.8%, P=0.001, respectively) and fibrosis score (23.7 vs 3.6%, P<0.001 and 18.1 vs 4.4%, P=0.002, respectively). The frequency of VDR a/a allele was also higher in patients with higher HBV DNA (11 vs 2.6%, P=0.002). Apa1 and Taq1 markers in VDR are in linkage-disequilibrium and 'at'haplotype is associated with severe liver disease. CONCLUSIONS: CCR5Delta32 heterozygosity was associated with susceptibility and VDR a/a, TNF-beta A/A with severity of HBV-related liver disease and VDR a/a allele with higher viral load. These results affirm an important role of immunogenetic factors in the outcome of chronic HBV infection.

PMID: 16545485 [PubMed - in process]

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Dan Med Bull. 2005 Dec;52(4):257.

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Cellular recognition of herpes simplex virus infection and virus-induced cytokine production.

Melchjorsen J.

Institute of Medical Microbiology and Immunology, The Bartholin Building, University of Aarhus, DK-8000 Arhus C. jesper@microbiology.au.dk.

The aim of the PhD dissertation was i) to determine the cytokine expression profile after herpes simplex virus (HSV) infection, ii) describe cellular mechanisms of viral recognition, and iii) identify viral proteins that inhibit or enhance cytokine production. The dissertation includes five papers published and two manuscripts intended for publication. HSV is a very common virus that clinically may manifest in gingivostomatitis, herpes labialis, keratitis, encephalitis, and genital herpes. Normally the infection is self-limiting but in immuno-compromised individuals, such as newborn babies, transplantation patients, and AIDS patients the virus may spread throughout the body and result in encephalitis, which is associated with high mortality and morbidity. i) The PhD study showed that HSV infection in dendritic cells and macrophages induces a number of well known proinflammatory cytokines, chemokines, and interferons, including the recently discovered type III interferons IL-28 and IL-29. The study also presents the first evidence that IL-29 has potential antiviral activity against HSV in human cells. Furthermore, selective production of the chemokine RANTES was seen in murine macrophages. ii) A group of recognition receptors, termed Toll-like receptors (TLRs), were investigated, and it was found that HSV infection was recognised through both TLR-dependent and TLR-independent mechanisms. Downstream of recognition, HSV-induced activation of the transcription factors IRF3 and NF-kappa-B was essential for chemokine and interferon expression. Furthermore, the kinases IKK-beta, TAK1, MEKK1, and PKR also play important roles for the virus-induced cytokine expression. iii) HSV evades the antiviral cytokine response through the viral protein infected cell protein (ICP) 27. Infection of macrophage cell cultures with ICP27-defective virus resulted in enhanced production of antiviral cytokines and an enhanced activation of NF-kappa-B and IRF3. However, the study also showed that virus replication is essential for cytokine expression and that viral ICP0 positively affects the expression of cytokines, such as the chemokine RANTES. In conclusion, viral gene products both enhance and restrict cytokine production. The project contributes with new knowledge on the progress of virus infections and may eventually contribute to better design of treatments and vaccines.

PMID: 16442008 [PubMed - in process]

 

Click here to readIL-2 increased RANTES production and CD25 expression in cultured PBMCs only from antiretroviral treated HIV-1+ patients with detectable viral loads.

Lozano JM, Kindelan JM, Cabello A, Gonzalez R, Solana R, Pena J.

Department of Immunology, Hospital "Reina Sofia", University of Cordoba, Spain; Department of Virology, Pasteur Institute of Paris, France.

In order to better understand the possible beneficial effects of intermittent IL-2 treatment as complement of antiretroviral therapy in HIV-1+ patients, we have measured the levels of RANTES in the supernatants and the CD25 expression in cultured PBMCs obtained from HIV-1+ individuals in presence of IL-2. The results showed a significant increases in RANTES production and in the expression of CD25+ in the cultures with IL-2 of PBMC obtained from HIV-1+ patients with a detectable viral load in comparison with both, HIV-1+ patients with no detectable viral loads and with healthy individuals. These results suggest that therapeutic IL-2 administered in addition to highly active anti-retroviral therapy (HAART) may contribute to increase the effect of this therapy by rising both RANTES production and CD25 expression only in HIV-1+ patients with detectable viral loads.

PMID: 16644491 [PubMed - in process]

Cancer Immunol Immunother. 2006 Apr 13; [Epub ahead of print]

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Tumor-derived CD4(+)CD25 (+) regulatory T cell suppression of dendritic cell function involves TGF-beta and IL-10.

Larmonier N, Marron M, Zeng Y, Cantrell J, Romanoski A, Sepassi M, Thompson S, Chen X, Andreansky S, Katsanis E.

Department of Pediatrics, Steele Children's Research Center, University of Arizona, 1501 N. Campbell Ave., P.O. Box 245073, Tucson, AZ, 85724-5073, USA, katsanis@peds.arizona.edu.

CD4(+)CD25(+) regulatory T cells have been characterized as a critical population of immunosuppressive cells. They play a crucial role in cancer progression by inhibiting the effector function of CD4(+) or CD8(+) T lymphocytes. However, whether regulatory T lymphocytes that expand during tumor progression can modulate dendritic cell function is unclear. To address this issue, we have evaluated the inhibitory potential of CD4(+)CD25(+) regulatory T cells from mice bearing a BCR-ABL(+) leukemia on bone marrow-derived dendritic cells. We present data demonstrating that CD4(+)CD25(+)FoxP3(+) regulatory T cells from tumor-bearing animals impede dendritic cell function by down-regulating the activation of the transcription factor NF-kappaB. The expression of the co-stimulatory molecules CD80, CD86 and CD40, the production of TNF-alpha, IL-12, and CCL5/RANTES by the suppressed DC is strongly down-regulated. The suppression mechanism requires TGF-beta and IL-10 and is associated with induction of the Smad signaling pathway and activation of the STAT3 transcription factor.

PMID: 16612596 [PubMed - as supplied by publisher]

J Biol Regul Homeost Agents. 2005 Jul-Dec;19(3-4):130-5.

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Rat peritoneal mast cells release regulated upon activation normal T cell expressed and secreted (RANTES) after TNF-alpha activation.

Kempuraj D, Petrarca C, Frydas S, Riccioni G, Conti P, Tete S, Vecchiet J.

Pharmacology Department, Medical School, Tufts University, Boston, MA, USA.

Chemokines are a family consisting of at least ten distinct novel 8-10 kD cytokines. The cysteine-cysteine (C-C) chemokines are chemoattractant and activators for monocytes, T cells and mast cells. RANTES is the prototype of the C-C chemokine subfamily, purified from different sources with chemoattractant and activator properties. In this study we found that supernatants derived from TNF-alpha (scalar concentrations)-activated rat peritoneal mast cell cultures (5 x 10(5)/mL), incubated overnight, produced high levels of RANTES. This data describes an additional mode of generation of RANTES. Moreover, RANTES mRNA was not significantly produced in untreated cells, while it was dramatically increased by calcium ionophore A23187, LPS and TNF-alpha compared with the controls. These results underscore the importance of the presence of mast cells for the production of RANTES in the inflammatory process and contribute to an understanding of the mechanism by which RANTES profoundly affects inflammatory responses in vivo.

PMID: 16602627 [PubMed - in process]

 

 

Interleukin 5, IL6, IL12, IFN-gamma, RANTES and Fractalkine in human nasal polyps, turbinate mucosa and serum.

Danielsen A, Tynning T, Brokstad KA, Olofsson J, Davidsson A.

Department of Otorhinolaryngology, Axess Medical Hospital, Oslo, Norway.

Polyps are considered to develop as an end result of an inflammatory process. Cytokines and chemokines in the respiratory mucosa may be a key to polyp pathophysiology. The main objective was to identify IL-5, IL-6, IL-12, RANTES, IFN-gamma and Fractalkine in humans on the protein level in nasal polyps and mucosa from the inferior turbinate (IT). Furthermore, the cytokines and chemokines RANTES and Fractalkine were analyzed in plasma. Tissue homogenates and plasma from 13 patients were analyzed by the ELISA technique. All the patients had longstanding nasal/paranasal polyposis. Fractalkine was detected in polyps and IT in two different patients. IL-5 was expressed in polyps and IT. IL-6 was expressed in all patients with a higher level in polyps than IT. IL-12 was present in plasma, polyps and IT, though at an increased level in polyps. RANTES was present at a higher level in plasma than in polyps and IT. IFN-gamma was detectable in polyps and IT. Fractalkine is detected in nasal polyps, which is a new observation. The overall results indicate a mixed T(H)1/T(H)2 cytokine profile in nasal polyps. RANTES and IL-12 are strongly present in plasma, suggesting an ongoing inflammatory "drive". IL-6 and IL-12 are up-regulated in polyps versus the IT. Up-regulation of IL-6 may be explained by increased fibroblast activity dependant on an ongoing local inflammation possibly initiated by an infection. IL-5, RANTES and IFN-gamma are equally represented in polyps and IT, indicating equilibrium between the nasal polyps and surrounding tissue, and that an up-regulation of cytokines in the polyp indicates a potential for polyp growth.


 

 

J Clin Pathol. 2006 Feb 10; [Epub ahead of print]

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Relation of p53, Bcl-2, Ki-67 and E-cadherin expressions in early invasive breast cancers with comedonecrosis (CN) as an accelerated apoptosis.

Hosaka N, Ryu T, Cui W, Li Q, Nishida A, Miyake T, Inaba M, Ikehara S.

Kansai Medical University, Japan.

AIMS: To study the relationship between comedonecrosis (CN) formation and morphology, apoptosis, and p53, Bcl-2, Ki-67 index and E-cadherin expression in early invasive breast cancer. Experimental design: We first divided early invasive breast cancers into two groups according to the presence (CN+ tumors) or absence (CN- tumors) of CN. Next, we examined the histological grade, apoptosis, and expressions of E-cadherin, Ki-67, p53 and Bcl-2 in the cancer area as well as in normal ducts (ND) from the specimen. RESULTS: CN+ tumors showed less tubule and gland formation than CN- tumors, although the histological grade was no different between the groups. Cells during early CN undergo apoptosis and subsequent necrosis. Whereas p53 was higher in CN+ tumors than in CN- tumors and ND, Bcl-2 was lower in CN+ tumors than in CN- tumors and ND. Ki-67 in both tumors were higher than in ND, but there was no difference between the tumors. E-cadherin in CN+ tumors was slightly higher than in CN- tumors, but lower than in ND. The level of CN was positively correlated with p53, but inversely correlated with Bcl-2 in all tumors, and p53and Bcl-2 were inversely correlated with each other. Furthermore, CN and p53 were correlated with Ki-67 in CN+ tumors, and Bcl-2 was correlated with Ki-67 in CN- tumors. CONCLUSION: CN may be actively regulated via an apoptotic procedure in massive cancers for their survival and progression, and the above proteins may be involved cooperatively in this process. CN+ and CN- tumors may have opposite proliferative systems under the p53-Bcl-2 pathway.

PMID: 16473926 [PubMed - as supplied by publisher]

 

J Biol Chem. 2006 Feb 9; [Epub ahead of print]

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Estrogen receptor-alpha binds p53 tumor suppressor protein directly and represses its function.

Liu W, Konduri SD, Bansal S, Nayak BK, Rajasekaran SA, Karuppayil SM, Rajasekaran AK, Das GM.

Pharmacology & Therapeutics, Roswell Park Cancer Institute, Buffalo, NY 14263.

Estrogen receptor-alpha (ERalpha) promotes cell proliferation of breast cancer cells whereas tumor suppressor protein p53 impedes proliferation of cells with genomic damage. Whether there is a direct link between these two antagonistic pathways has remained unclear. Here we report that ERalpha binds directly to p53 and negatively regulates its function. The activation function-2 (AF-2) domain of ERalpha and the C-terminal regulatory domain of p53 are necessary for the interaction. Knocking down p53 and ERalpha by small interfering RNA (siRNA) elicits opposite effects on p53-target gene expression and cell cycle progression. Remarkably, ionizing radiation that causes genomic damage disrupts the interaction between ERalpha and p53. Ionizing radiation together with ERa knock down results in an additive effect on transcription of endogenous p53-target gene p21 (CDKN1) in human breast cancer cells. Our findings reveal a novel mechanism for regulating p53 and suggest that suppressing p53 function is an important component in the pro-proliferative role of ERalpha.

PMID: 16469747 [PubMed - as supplied by publisher]

 

 

 

Relation of p53, Bcl-2, Ki-67 and E-cadherin expressions in early invasive breast cancers with comedonecrosis (CN) as an accelerated apoptosis.

Hosaka N, Ryu T, Cui W, Li Q, Nishida A, Miyake T, Inaba M, Ikehara S.

Kansai Medical University, Japan.

AIMS: To study the relationship between comedonecrosis (CN) formation and morphology, apoptosis, and p53, Bcl-2, Ki-67 index and E-cadherin expression in early invasive breast cancer. Experimental design: We first divided early invasive breast cancers into two groups according to the presence (CN+ tumors) or absence (CN- tumors) of CN. Next, we examined the histological grade, apoptosis, and expressions of E-cadherin, Ki-67, p53 and Bcl-2 in the cancer area as well as in normal ducts (ND) from the specimen. RESULTS: CN+ tumors showed less tubule and gland formation than CN- tumors, although the histological grade was no different between the groups. Cells during early CN undergo apoptosis and subsequent necrosis. Whereas p53 was higher in CN+ tumors than in CN- tumors and ND, Bcl-2 was lower in CN+ tumors than in CN- tumors and ND. Ki-67 in both tumors were higher than in ND, but there was no difference between the tumors. E-cadherin in CN+ tumors was slightly higher than in CN- tumors, but lower than in ND. The level of CN was positively correlated with p53, but inversely correlated with Bcl-2 in all tumors, and p53and Bcl-2 were inversely correlated with each other. Furthermore, CN and p53 were correlated with Ki-67 in CN+ tumors, and Bcl-2 was correlated with Ki-67 in CN- tumors. CONCLUSION: CN may be actively regulated via an apoptotic procedure in massive cancers for their survival and progression, and the above proteins may be involved cooperatively in this process. CN+ and CN- tumors may have opposite proliferative systems under the p53-Bcl-2 pathway.

PMID: 16473926 [PubMed - as supplied by publisher]