Lymphocyte GH-axis hormones in immunity

Weigent, Douglas A.

doi:10.1016/j.cellimm.2013.10.003

Cited by 55 publications

(44 citation statements)

References 185 publications

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“…Since the increase was independent of mutant APP/PS1 expression, one possible explanation is that loss of regulatory behaviors from GH/IGF-1, PRL, or TSH were responsible for the elevated cytokine levels. Although we did not observe any ability of these factors to modify microglial secretion in vitro , they are potent immunomodulators (Colaianni, et al, 2013,Costanza, et al, 2015,Spaziani, et al, 2014,van der Weerd, et al, 2014,Weigent, 2013,Wu, et al, 2014). Moreover, an increase in brain inflammatory cytokine levels, particularly IL-1β and TNFα, has been shown to have an ability to decrease Aβ plaque deposition in two different mouse models of AD (Chakrabarty, et al, 2011,Shaftel, et al, 2007).…”

Section: 0 Discussioncontrasting

confidence: 81%

The Ames dwarf mutation attenuates Alzheimer's disease phenotype of APP/PS1 mice

Puig

Kulas

Franklin

et al. 2016

Neurobiology of Aging

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APP/PS1 double transgenic mice expressing human mutant amyloid precursor protein (APP) and presenilin-1 (PS-1) demonstrate robust brain Aβ peptide containing plaque deposition, increased markers of oxidative stress, behavioral dysfunction, and proinflammatory gliosis. On the other hand, lack of growth hormone, prolactin, and thyroid-stimulating hormone due to a recessive mutation in the Prop 1 gene (Prop1df) in Ames dwarf mice results in a phenotype characterized by potentiated anti-oxidant mechanisms, improved learning and memory, and significantly increased longevity in homozygous mice. Based upon this, we hypothesized that a similar hormone deficiency might attenuate disease changes in the brains of APP/PS1 mice. To test this idea, APP/PS1 mice were crossed to the Ames dwarf mouse line. APP/PS1, wild type, df/+, df/df, df/+/APP/PS1, and df/df/APP/PS1 mice were compared at 6 months of age through behavioral testing and assessing amyloid burden, reactive gliosis, and brain cytokine levels. df/df mice demonstrated lower brain growth hormone (GH) and insulin-like growth factor 1 (IGF-1) concentrations. This correlated with decreased astrogliosis and microgliosis in the df/df/APP/PS1 mice and, surprisingly, reduced Aβ plaque deposition and Aβ 1-40 and Aβ 1-42 concentrations. The df/df/APP/PS1 mice also demonstrated significantly elevated brain levels of multiple cytokines in spite of the attenuated gliosis. These data indicate that the df/df/APP/PS1 line is a unique resource in which to study aging and resistance to disease and suggest that the affected pituitary hormones may have a role in regulating disease progression.

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Section: 0 Discussioncontrasting

confidence: 81%

The Ames dwarf mutation attenuates Alzheimer's disease phenotype of APP/PS1 mice

Puig

Kulas

Franklin

et al. 2016

Neurobiology of Aging

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“…These results agree with earlier findings that GHRH-R antagonists suppress inflammation by reducing the production of inflammatory proteins, such as IL-β, NF-κB/p65, and COX-2, in experimental prostatic hyperplasia and breast cancer (15,18) and alleviate inflammation-triggered oxidative stress by increasing glutathione and decreasing glutathione peroxidase activity (29). The antagonist may alleviate inflammatory responses by acting as a local modulator for the maturation and migration of immune cells, including macrophages, lymphocytes, and other leukocytes (30)(31)(32). Because GH has been shown to target macrophages to trigger various immune responses (15), we argue that the GHRH-R antagonist may block the signaling of GHRH-R on the macrophages residing in the iris-CB and so inhibit synthesis and release of GH, resulting in reduced IGF1 secretion.…”

Section: Discussionmentioning

confidence: 94%

Antagonist of GH-releasing hormone receptors alleviates experimental ocular inflammation

Qin¹,

Chan

Chong

et al. 2014

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

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Disruptions in immunity and occurrence of inflammation cause many eye diseases. The growth hormone-releasing hormone-growth hormone-insulin-like growth factor-1 (GHRH-GH-IGF1) axis exerts regulatory effects on the immune system. Its involvement in ocular inflammation remains to be investigated. Here we studied this signaling in endotoxin-induced uveitis (EIU) generated by LPS. The increase in GHRH receptor (GHRH-R) protein levels was parallel to the increase in mRNA levels of pituitary-specific transcription factor-1, GHRH-R splice variant 1, GHRH, and GH following LPS insult. Elevation of GHRH-R and GH receptor was localized on the epithelium of the iris and ciliary body, and GHRH-R was confined to the infiltrating macrophages and leukocytes in aqueous humor but not to those in stroma. Treatment with GHRH-R antagonist decreased LPS-stimulated surges of GH and IGF1 in aqueous humor and alleviated inflammation by reducing the infiltration of macrophages and leukocytes and the production of TNF-α, IL-1β, and monocyte chemotactic protein-1. Our results indicate that inflammation in the iris and ciliary body involves the activation of GHRH signaling, which affects the recruitment of immune cells and the production of proinflammatory mediators that contribute to EIU pathogenesis. Moreover, the results suggest that GHRH-R antagonists are potential therapeutic agents for the treatment of acute ocular inflammation.

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“…Growth hormone (GH) and insulin-like growth factor 1 (IGF-1) Several neuroendocrine hormones have been shown to mediate important effects on the immune system. GH, also known as somatotropin, is a peptide hormone primarily secreted by the anterior pituitary gland (150); although interestingly, a previous study has also reported that GH can be produced by ex vivo isolated human thymocytes and TECs (151). The potent effects of GH on thymic function have been extensively investigated using GH deficient mice, which exhibit defects in T-cell development.…”

Section: Interleukin-22 (Il-22)mentioning

confidence: 99%

Thymus: the next (re)generation

Chaudhry

Velardi

Dudakov

et al. 2016

Immunological Reviews

145

131

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Summary As the primary site of T cell development, the thymus plays a key role in the generation of a strong yet self-tolerant adaptive immune response, essential in the face of the potential threat from pathogens or neoplasia. As the importance of the role of the thymus has grown, so too has the understanding that it is extremely sensitive to both acute and chronic injury. The thymus undergoes rapid degeneration following a range of toxic insults, and also involutes as part of the aging process, albeit at a faster rate than many other tissues. The thymus is, however, capable of regenerating, restoring its function to a degree. Potential mechanisms for this endogenous thymic regeneration include keratinocyte growth factor (KGF) signaling, and a more recently described pathway in which innate lymphoid cells produce interleukin-22 (IL-22) in response to loss of double positive thymocytes and upregulation of IL-23 by dendritic cells. Endogenous repair is unable to fully restore the thymus, particularly in the aged population, and this paves the way towards the need for exogenous strategies to help regenerate or even replace thymic function. Therapies currently in clinical trials include KGF, use of the cytokines IL-7 and IL-22, and hormonal modulation including growth hormone administration and sex steroid inhibition. Further novel strategies are emerging in the pre-clinical setting, including the use of precursor T cells and thymus bioengineering. The use of such strategies offers hope that for many patients, the next regeneration of their thymus is a step closer.

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Lymphocyte GH-axis hormones in immunity

Cited by 55 publications

References 185 publications

The Ames dwarf mutation attenuates Alzheimer's disease phenotype of APP/PS1 mice

The Ames dwarf mutation attenuates Alzheimer's disease phenotype of APP/PS1 mice

Antagonist of GH-releasing hormone receptors alleviates experimental ocular inflammation

Thymus: the next (re)generation

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