TNF-α downregulates murine hepatic growth hormone receptor expression by inhibiting Sp1 and Sp3 binding

Denson, Lee A.; Menon, Ram K.; Shaufl, Angel L.; Bajwa, Himmat S.; Williams, Carol R.; Karpen, Saul J.

doi:10.1172/jci10994

Cited by 97 publications

(86 citation statements)

References 30 publications

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“…46,47 The reduced levels of Sp1 binding with TNF-␣ stimulation could also be attributable to TNF-␣-induced Sp1 phosphorylation ( Figure 7B) because Sp1 phosphorylation could reduce Sp1 binding 48 and dephosphorylation of Sp1 has been suggested to enhance Sp1 DNA binding activity. 49 In DSS-treated mice, we found that DSS does not alter overall nuclear levels of Sp1, similar studies showed that TNF-␣ did not change Sp1 expression 30 but increased NF-B (p65) expression. 50 Similarly, DSS treatment can up-regulate the expression of NF-B (p65) in colon epithelial cells, and more importantly, DSS treatment can translocate p65 protein into nucleus as active form, which suggests that the increased expression of SPAK might be attributable to the increased nuclear protein NF-B (p65).…”

Section: Discussionsupporting

confidence: 68%

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Nuclear Factor-κB Is a Critical Mediator of Ste20-Like Proline-/Alanine-Rich Kinase Regulation in Intestinal Inflammation

Yan

Dalmasso

Nguyen

et al. 2008

The American Journal of Pathology

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Section: Discussionsupporting

confidence: 68%

“…This indicates that TNF-␣ might reduce Sp1 expression levels or inhibit the binding of Sp1 to oligonucleotides. 30 However, as shown in Figure 6C, TNF-␣ treatment increases NF-B (p65) binding to the corresponding oligonucleotides.…”

Section: The Transcription Factors Sp1 and Nf-b Are Physically Associmentioning

confidence: 84%

Nuclear Factor-κB Is a Critical Mediator of Ste20-Like Proline-/Alanine-Rich Kinase Regulation in Intestinal Inflammation

Yan

Dalmasso

Nguyen

et al. 2008

The American Journal of Pathology

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“…1 We asked whether the GH-dependent STAT5b transcription factor, which we have recently linked to growth failure in colitis, might also regulate mucosal inflammation. 30,38 In the current study, we have identified a novel anti-inflammatory STAT5b-dependent pathway in the colon in children with newly diagnosed CD and in murine colitis.…”

Section: Discussionmentioning

confidence: 78%

Signal Transducer and Activator of Transcription 5b Promotes Mucosal Tolerance in Pediatric Crohn's Disease and Murine Colitis

Han

Osuntokun

Benight

et al. 2006

The American Journal of Pathology

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Growth hormone (GH) regulates anabolic metabolism via activation of the STAT5b transcription factor and reduces mucosal inflammation in colitis.Peroxisome proliferator-activated receptor (PPAR) ␥ suppresses mucosal inflammation and is regulated by GH through STAT5b. We hypothesized that the GH:STAT5b axis influences susceptibility to colitis via regulation of local PPAR␥ abundance. Colon biopsies from children with newly diagnosed Crohn's disease (CD) and controls were exposed to GH in short-term organ culture. Trinitrobenzene sulfonic acid (TNBS) administration was used to induce colitis in STAT5b-deficient mice and wildtype controls , with and without rosiglitazone pretreatment. GH receptor , STAT5b , PPAR␥ , and nuclear factor B activation and expression were determined. Epithelial cell GH receptor expression and GH-dependent STAT5b activation and PPAR␥ expression were reduced in CD colon. STAT5b-deficient mice exhibited reduced basal PPAR␥ nuclear abundance and developed more severe proximal colitis after TNBS administration. This was associated with a significant increase in mucosal nuclear factor B activation at baseline and after TNBS administration. Rosiglitazone ameliorated colitis in wild-type mice but not STAT5b-deficient mice. GHdependent STAT5b activation is impaired in affected CD colon and contributes to chronic mucosal inflammation via down-regulation of local PPAR␥ expression. Therapeutic activation of the GH:STAT5b axis therefore represents a novel target for restor- Current evidence suggests that Crohn's disease (CD) is caused by loss of tolerance to the enteric flora, leading to chronic inflammation and intestinal damage.1 Increased epithelial nuclear factor B (NF-B) activity and consequent chemokine expression are fundamental molecular features of this loss of tolerance. Increased NF-B DNAbinding activity has been attributed to increased binding of the p50 and p65 subunits.2 Importantly, disease activity in mice with colitis due to 2,4,6-trinitrobenzene sulfonic acid (TNBS) administration was inhibited by antisense oligonucleotides that inhibit p65 expression.2 These studies suggest a critical role for NF-B in mediating expression of proinflammatory factors, which are central to the pathogenesis of CD. Although much less is known regarding the regulatory transcription factors that may promote mucosal tolerance, recent studies have suggested that both STAT5a/b and peroxisome proliferator-activated receptor (PPAR) ␥ may play a role.Colonic mRNA expression of the STAT5b transcription factor is down-regulated in affected segments in adults with CD and ulcerative colitis.3 However, the functional significance of this is not known. Moreover, whether GHdependent STAT5b tyrosine phosphorylation and DNA binding are reduced in affected CD colon has not been determined. Current data suggest that the closely related STAT5a and STAT5b transcription factors are required, in

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“…A promoter assay revealed that Sp1/Sp3-binding sites of CD2AP-promoter regions is required for up-regulation of CD2AP [34], while inflammatory cytokines, such as TNF-, suppresses various genes via inhibiting Sp1/Sp3-DNA binding [6]. Thus, cytokine-mediated inactivation of Sp1/Sp3-binding promoter sites may cause the loss of CD2AP during septic ARF, and future studies would shed light on this speculation.…”

Section: Discussionmentioning

confidence: 95%

Decreases in Podocin, CD2-Associated Protein (CD2AP) and Tensin2 May Be Involved in Albuminuria during Septic Acute Renal Failure

Kato

Mizuno-Horikawa

Mizuno

2011

The Journal of Veterinary Medical Science

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ABSTRACT. Podocytes have a peculiar structure constituting slit diaphragm (SD) and foot process (FP), and play essential roles in the glomerular filtration barrier. There is now ample evidence that SD-and FP-associated molecules, such as podocin and CD2-associated protein (CD2AP), are down-regulated during albuminuria of chronic kidney disease. However, it is still unclear whether these molecules are altered during acute renal failure (ARF) with albuminuria. Using lipopolysaccharide (LPS)-treated mice as a model of septic ARF, we provide evidence that the expression of SD-and FP-associated molecules becomes faint, along with albuminuria. In the LPS-treated mice, urinary albumin levels gradually increased, associated with the elevation of blood urea nitrogen levels, indicating the successful induction of albuminuria during septic ARF. In this pathological process, glomerular podocin expression became faint, especially at 36 hr post-LPS challenge (i.e., a peak of albuminuria). Likewise, LPS treatment led to a significant decrease in CD2AP, an anchorage between podocin and F-actin. With regard to this, tensin2 is a novel molecule that stabilizes F-actin extension. Interestingly, glomerular tensin2 expression levels were also decreased during the albuminuric phase, associated with losses of glomerular F-actin and synaptopodin under septic states. As a result, there were some lesions of podocytic FP effacement, as shown by electron microscopy. Based on these data, we emphasize the importance of concomitant decreases in podocin, CD2AP and tensin2 during septic ARF-associated proteinuria.

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TNF-α downregulates murine hepatic growth hormone receptor expression by inhibiting Sp1 and Sp3 binding

Cited by 97 publications

References 30 publications

Nuclear Factor-κB Is a Critical Mediator of Ste20-Like Proline-/Alanine-Rich Kinase Regulation in Intestinal Inflammation

Nuclear Factor-κB Is a Critical Mediator of Ste20-Like Proline-/Alanine-Rich Kinase Regulation in Intestinal Inflammation

Signal Transducer and Activator of Transcription 5b Promotes Mucosal Tolerance in Pediatric Crohn's Disease and Murine Colitis

Decreases in Podocin, CD2-Associated Protein (CD2AP) and Tensin2 May Be Involved in Albuminuria during Septic Acute Renal Failure

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