Inflammatory cytokines and acquiredgrowth hormone resistance

Laue, S. Von; Ross, R. J. M.

doi:10.1016/s1096-6374(00)80003-9

Cited by 17 publications

(12 citation statements)

References 78 publications

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“…However, the possible link of low IGF-I with inflammation beyond the confounding effects of MS and age in the setting of psoriasis had not been previously demonstrated. For the first time we found that the low IGF-I status in psoriatic patients was present independently of age and classical criteria of MS. Apart from age, it is well-known that different factors, such as glucose homeostasis (19) and inflammation (6,12), have been reported to affect IGF-I metabolism IGF-I, while up to 90% circulating IGF-I originates in the liver (19).…”

Section: Discussionmentioning

confidence: 99%

“…Although the relationship between IGF-I and cardiovascular disease is still unknown, a protective role in the development of atherosclerosis was suggested for free IGFI levels (24). Taking into account the involvement of inflammatory cytokines in IGF-I regulation (6,12), particularly of visceral fat-derived adipocytokines, the results on the relationship between IGF-I, psoriasis and inflammation, the three main variables of the study, led us to hypothesize that: i) low IGF-I may represent a consequence of the psoriasis-related inflammatory state; ii) the inverse relationship between IGF-I and PASI might represent an epiphenomenon of the psoriasis-related inflammatory state; iii) the inverse correlation between IGF-I and VAl suggests the involvement of the. adipocytes dysfunction in low IGF-I status more than MS per se; iiii) low IGF-I, may be involved in the increased cardiometabolic risk in psoriasis, similarly to aging (22), obesity and type 2 diabetes (23), CVD (21), and cystic fibrosis (25).…”

Section: Discussionmentioning

confidence: 99%

“…It is well known that a number of inflammatory cytokines affect insulin-like growth factor (IGF)-I secretion (6), the main anabolic mediator of somatotroph axis. IGF-l has been reported to act as an autocrine/paracrine essential signal for proliferation of epidermal keratinocytes (7), and lGF-1 has been found to be overproduced in psoriatic epidermis (8)(9).…”

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confidence: 99%

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Insulin-like Growth Factor-1, Psoriasis, and Inflammation: A Ménage à Trois?

et al. 2011

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Psoriatic patients have an accumulation of metabolic syndrome (MS) and cardiovascular diseases (CVD), likely mediated by systemic inflammation, and exhibiting low circulating levels of insulin-like growth factor (IGF)-I, a marker of MS and CVD in the general population. The aim of this study is to determine the association of IGF-I and inflammation, and to assess the cardio-metabolic risk calculating the visceral adiposity index (VAI), in a group of psoriatic patients without MS. IGF-I, fibrinogen, C-reactive protein (CRP), and interleukin (IL)-6 levels were determined in 20 patients with moderate to severe psoriasis (age range 23–77 yrs) without MS, according to criteria of the National Cholesterol Education Program's Adult Panel III (ATP III), and 20 age- and BMI-matched controls. The standard deviation score (SDS) of IGF-I levels according to age (zSDS), the homeostasis model assessment of insulin resistance (HOMA-IR), the whole-body insulin sensitivity index (ISI), and VAI were also calculated. Psoriasis Area and Severity Index (PASI) mean value was 17.8±11. HDL cholesterol and IGF-I zSDS values were lower (p<0.001) and waist circumference (p<0.001), VAI, fibrinogen, and IL-6 (p<0.005) were higher compared with controls, while HOMA-IR and ISI were not statistically different. Lower IGF-I zSDS values were associated to higher values of BMI (p=0.04), waist circumference, VAI (p<0.001), PASI (p=0.011), or IL-6 (p<0.001). At the multivariate analysis PASI was the major determinant of IGF-I zSDS (p=0.016), accounting for 37% of its variability. In a subset of psoriatic patients without MS, chronic inflammation might be an important modulator of low IGF-I status, as a further possible mechanistic link between psoriasis and associated metabolic co-morbidities. The negative correlation between age-related IGF-I values and VAI suggest the involvement of adipocyte dysfunction in low IGF-I status more than MS per se. Further studies are needed to address whether these results are valid also for other psoriatic patients.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Insulin-like Growth Factor-1, Psoriasis, and Inflammation: A Ménage à Trois?

et al. 2011

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“…deleted mice, GH-mediated STAT5 activation is enhanced and the animals grow larger than the wild-type mice (31). Proinflammatory cytokines also stimulate SOCS expression and in this way can inhibit GH action (32,33). Because the serum CRP levels were elevated significantly in the CRF animals, the increase in SOCS2 and CIS expression may have arisen in part because of heightened inflammatory cytokine activity (20).…”

Section: Discussionmentioning

confidence: 99%

Chronic Uremia Attenuates Growth Hormone–Induced Signal Transduction in Skeletal Muscle

Sun

Zheng²,

Tummala³

et al. 2004

Journal of the American Society of Nephrology

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Abstract. Malnutrition and muscle wasting are common in chronic renal failure (CRF) and adversely affect morbidity and mortality. Contributing to the muscle wasting is resistance to growth hormone (GH). For testing whether impaired GH signaling is a cause of the skeletal muscle GH resistance and for elucidating its mechanisms, muscle GH signaling and action were studied in GH-deficient rats with surgically induced CRF and sham-operated pairfed control rats. GH treatment increased gastrocnemius muscle IGF-1 mRNA levels significantly in control but not in CRF rats. GH-activated Janusassociated kinase 2 (JAK2)-signal transducers and activators of transcription 5 (STAT5) signaling was impaired in CRF rats, despite normal GH receptor (GHR), JAK2, and STAT5 protein levels. Phosphorylation of the GHR, JAK2, and STAT5 in response to GH was depressed by nearly half in CRF (P Ͻ 0.05), and nuclear phospho-STAT5 levels were depressed by approximately one third (P Ͻ 0.01). GH-stimulated suppressors of cytokine signaling 2 mRNA levels were significantly higher in CRF. This may be related to inflammatory cytokine activity because C-reactive protein levels were elevated. Muscle protein-tyrosine phosphatase activity was also increased significantly by twofold. In conclusion, rats with CRF acquire skeletal muscle resistance to GH that is caused at least in part by impaired JAK2-GHR-STAT5 phosphorylation and nuclear STAT5 translocation. Furthermore, it seems that the attenuated JAK2-STAT5 phosphorylation may be caused by at least two different processes. One involves depressed phosphorylation of the signaling proteins because of increased suppressors of cytokine signaling 2 expression that may be linked to lowgrade inflammation. The other may involve increased signaling protein dephosphorylation because of heightened protein-tyrosine phosphatase activity.Advanced chronic renal failure (CRF) is often complicated by the appearance of muscle wasting and malnutrition, conditions that have a distinct adverse effect on morbidity and mortality (1,2). Several factors contribute to the development and perpetuation of the wasted state, including anorexia with reduced calorie and protein intake; acidosis; inadequate dialysis with accumulation of toxic products; inflammatory cytokines; diabetes; cardiac failure; loss of amino acids in the dialysate; and resistance to anabolic hormones such as insulin, growth hormone (GH), and IGF-I which is worsened by malnutrition and inflammation (3-5). To some extent, insensitivity to GH can be overcome by pharmacologic doses of recombinant GH, but this does increase the risk of adverse events. Several small studies have demonstrated that GH treatment of adult ESRD patients produces a salutary effect on urea kinetics, protein turnover, and lean body mass (6,7). In children with advanced CRF, GH resistance is a major cause of impaired body growth, and this can largely be corrected by GH treatment (8 -10).The mechanisms that account for the development of GH resistance in uremia are not well understood (10 -...

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“…Apart from promoting longitudinal body growth, GHR signalling regulates metabolism and cellular functions such as proliferation and differentiation [1]. Excessive GH signalling has been connected to cancer [4,5], whereas GH insensitivity has been reported in cachexia patients [6,7], which demonstrates the importance of a proper GH sensitivity control. Cachexia is a complex metabolic disorder, occurring in cancer and AIDS patients, characterized by extensive loss of muscle mass and decreased quality of life [8,9].…”

Section: Introductionmentioning

confidence: 99%

βTrCP interacts with the ubiquitin-dependent endocytosis motif of the GH receptor in an unconventional manner

Almeida

Hocking

Boelens

et al. 2013

Biochemical Journal

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GH (growth hormone) binding to the GHR (GH receptor) triggers essential signalling pathways that promote growth and metabolic regulation. The sensitivity of the cells to GH is mainly controlled by the endocytosis of the receptor via βTrCP (β-transducin repeat-containing protein). In the present study, we show that βTrCP interacts directly via its WD40 domain with the UbE (ubiquitin-dependent endocytosis) motif in GHR, promoting GHR ubiquitination in vitro. NMR experiments demonstrated that the UbE motif is essentially unstructured, and, together with functional mapping of the UbE and βTrCP WD40 residues necessary for binding, led to a unique interaction model of βTrCP with GHR-UbE. This interaction is different from the conventional βTrCP-substrate interactions described to date. This interaction therefore represents a promising specific target to develop drugs that inhibit GHR endocytosis and increase GH sensitivity in cachexia patients.

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Inflammatory cytokines and acquiredgrowth hormone resistance

Cited by 17 publications

References 78 publications

Insulin-like Growth Factor-1, Psoriasis, and Inflammation: A Ménage à Trois?

Insulin-like Growth Factor-1, Psoriasis, and Inflammation: A Ménage à Trois?

Chronic Uremia Attenuates Growth Hormone–Induced Signal Transduction in Skeletal Muscle

βTrCP interacts with the ubiquitin-dependent endocytosis motif of the GH receptor in an unconventional manner

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