Tumor Necrosis Factor α Blockade Restores Growth Hormone Signaling in Murine Colitis

DiFedele, Lisa; He, Jianqiao; Bonkowski, Erin; Han, Xiaonan; Held, Matthew A.; Bohan, Alan; Menon, Ram K.; Denson, Lee A.

doi:10.1053/j.gastro.2005.02.003

Cited by 67 publications

(77 citation statements)

References 46 publications

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“…Because we have recently shown that GH activation of STAT5b and IGF-1 is reduced in liver in murine colitis, we asked whether the GH:STAT5b:PPAR␥ pathway would similarly be reduced in inflamed colon. 30 We found that GH-dependent STAT5b activation and PPAR␥ mRNA expression were significantly reduced in the affected colon of children with CD at diagnosis. IF identified a high constitutive expression of activated STAT5 and PPAR␥ in CECs and subepithelial LPMs of healthy controls, relative to a reduction in both cell populations in CD.…”

Section: Discussionmentioning

confidence: 70%

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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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Section: Discussionmentioning

confidence: 70%

“…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: 76%

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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“…The mechanism underlying the effects of GH on disease activity in this experimental model may involve an increased association between gp130 and SHP-2 and down-regulation of constitutively active STAT3 . The investigators involved in this study also reported, using the same animal model, that blocking the actions of TNF-␣ with a neutralizing antibody could up-regulate hepatic IGF-I production and GH receptor expression and enhance GH-dependent STAT5 activation (DiFedele et al, 2005). In contrast, TNF-␣ reduced the abundance of GH receptors and attenuated STAT5 phosphorylation in cultured rat hepatocytes (DiFedele et al, 2005).…”

Section: Other Autoimmune Diseasesmentioning

confidence: 81%

Insulin-Like Growth Factor-I Regulation of Immune Function: A Potential Therapeutic Target in Autoimmune Diseases?

2010

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“…GH stimulates in vitro T and B-cell proliferation (5) and Ig synthesis (6); enhances human myeloid progenitor cell maturation (7); and modulates in vivo Th1/Th2 (8) and humoral immune responses (1). In addition, therapeutic activation of the GH/STAT5B axis is postulated as a target for restoring mucosal tolerance in Crohn disease (9,10). A single point mutation in STAT5B limits its DNA binding activity as well as maintenance of FOXP3 expression by Treg cells in nonobese diabetic (NOD) mice (11).…”

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confidence: 99%

Growth hormone prevents the development of autoimmune diabetes

Villares

Kakabadse

Juarranz

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Evidence supports a relationship between the neuroendocrine and the immune systems. Data from mice that overexpress or are deficient in growth hormone (GH) indicate that GH stimulates T and B-cell proliferation and Ig synthesis, and enhances maturation of myeloid progenitor cells. The effect of GH on autoimmune pathologies has nonetheless been little studied. Using a murine model of type 1 diabetes, a T-cell-mediated autoimmune disease characterized by immune cell infiltration of pancreatic islets and destruction of insulin-producing β-cells, we observed that sustained GH expression reduced prodromal disease symptoms and eliminated progression to overt diabetes. The effect involves several GH-mediated mechanisms; GH altered the cytokine environment, triggered anti-inflammatory macrophage (M2) polarization, maintained activity of the suppressor T-cell population, and limited Th17 cell plasticity. In addition, GH reduced apoptosis and/or increased the proliferative rate of β-cells. These results support a role for GH in immune response regulation and identify a unique target for therapeutic intervention in type 1 diabetes.beta cells | Tregs G rowth hormone (GH) is a pleiotropic hormone that affects a broad spectrum of physiological functions, from carbohydrate and lipid metabolism to the immune response (1). Several studies have linked GH with autoimmune diseases, although its effects on the immune system are still debated. Whereas some reports using GH-deficient mice indicate that it does not affect immune competence (2), others suggest that GH is necessary for correct immune system development (1, 3). The GH receptor (GHR) is expressed by several lymphocyte subpopulations (4). GH stimulates in vitro T and B-cell proliferation (5) and Ig synthesis (6); enhances human myeloid progenitor cell maturation (7); and modulates in vivo Th1/Th2 (8) and humoral immune responses (1). In addition, therapeutic activation of the GH/STAT5B axis is postulated as a target for restoring mucosal tolerance in Crohn disease (9, 10). A single point mutation in STAT5B limits its DNA binding activity as well as maintenance of FOXP3 expression by Treg cells in nonobese diabetic (NOD) mice (11). These mice develop type 1 diabetes, which is characterized by autoimmune destruction of pancreatic β-cells due to the effect of environmental factors on genetically predisposed individuals (12,13). Although this murine model does not completely mimic the human disease, most steps in the pathogenesis, including prodromal and clinical symptoms, are closely comparable (14).Despite the interdependence of GH and insulin regulation and the known effects of GH and insulin-like growth factor 1 (IGF1) on pancreatic β-cell survival, proliferation and neogenesis (15, 16), hormone influences have not been described in type 1 diabetes; no specific studies have addressed the consequences of long-term GH replacement therapy in this disease. Here we show the effects of long-term GH supplementation as a tool to modulate autoimmune attack on pancreatic β-cells. NOD...

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Tumor Necrosis Factor α Blockade Restores Growth Hormone Signaling in Murine Colitis

Cited by 67 publications

References 46 publications

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

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

Insulin-Like Growth Factor-I Regulation of Immune Function: A Potential Therapeutic Target in Autoimmune Diseases?

Growth hormone prevents the development of autoimmune diabetes

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