Reversible inhibitory effects and absence of toxicity of the tetrapeptide acetyl-N-Ser-Asp-Lys-Pro (AcSDKP) in human long-term bone marrow culture.
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We studied the effects of tumor necrosis factor-alpha (TNF alpha), a macrophage-derived pleiotropic cytokine produced during the inflammatory/immune response, on the function of the hypothalamic-pituitary-adrenal (HPA) axis of the rat. Intravenous injections of TNF alpha stimulated plasma ACTH and corticosterone secretion in a dose-dependent fashion. This effect was inhibited by a rat CRH antiserum that was administered to the rats 1 h before the TNF alpha injections. This suggested that CRH is a major mediator of the HPA axis response to TNF alpha. We subsequently evaluated the ability of TNF alpha to influence CRH and ACTH secretion in vitro by explanted rat hypothalami in organ culture and by dispersed rat anterior pituicytes in primary culture respectively. Hypothalami were incubated for 40 min with graded concentrations of TNF alpha (10 pM to 1 microM). This cytokine stimulated CRH secretion in a dose-dependent fashion, with an EC50 of 6.7 x 10 pM (P less than 0.05). Preincubation of hypothalamic explants with dexamethasone, indomethacin (1 microM), eicosatetraynoic acid (10 microM), or nordihydroguaiaretic acid (30 microM) resulted in inhibition of TNF alpha-stimulated CRH secretion (P less than 0.05). Interestingly, 4-h incubation with TNF alpha had no effect on ACTH secretion from rat anterior pituicytes at a concentration of 10 nM. Higher concentrations of TNF alpha (100 nM and 1 microM), however, elicited a dose-dependent increase in the ACTH concentration in the medium. Our results suggest that TNF alpha represents one of the immune response mediators that directly or via stimulation of other cytokines act as activators of the HPA axis during immune/inflammatory reactions. This effect appears to be glucocorticoid suppressible and eicosanoid mediated. The primary site of action of TNF alpha appears to by the hypothalamic CRH-secreting neuron. Some pituitary and adrenal effects of TNF alpha, however, cannot be excluded.
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Tumor necrosis factor-α (TNF) and interleukin-1 β (IL-1) are secreted by activated monocytes and other immune cells. Since IL-1 has been shown to elevate rat plasma ACTH and both of these cytokines induce similar acute-phase responses, the present studies of TNF were undertaken to characterize the ACTH response to this immune cell product. Human rTNF, administered iv at doses (100-1000 ng) which failed to affect blood pressure, food consumption or prolactin levels, resulted in significant peak elevations of rat plasma ACTH within 20 min (mean ± SE 304+94 and 958 ± 128 pg/ml for 100 and 1000 ng, respectively, compared to 53 ± 16 pg/ml for vehicle). rTNF from two different sources produced similar elevations of ACTH as an equivalent amount of rIL-1. TNF failed to affect cultured anterior pituicytes, and it did not modify the response to CRF. When administered into the upper third cerebroventricle, TNF 20 ng failed to affect ACTH levels whereas IL-1 30 ng raised ACTH to 638 ± 79 pg/ml compared to 177 ± 24 pg/ml for vehicle (p < 0.001). Furthermore, intraparenchymal injection of IL-1, directly above the median eminence, elevated ACTH to 484 ± 93 pg/ml; again, TNF was completely ineffective. Thus, TNF-α and IL-1β are both potent ACTH secretagogues with complementary modes of action; however, the proximate target of TNF action appears to be peripheral to the CNS and pituitary whereas that of IL-1 appears to be the median eminence.
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Intimate contact between haemopoietic progenitor cells and elements of the bone marrow stroma is required for progenitor cell proliferation and differentiation. It is believed that the stroma provides particular niches for the development of haemopoietic cells of different lineages. Cytokines, stromal cell surface molecules and molecules of the stromal extracellular matrix all contribute to defining these mi-croenvironmental niches. Data obtained using an in vitro model of haemopoiesis support the view that progenitor cell adhesion to stroma is mediated by multiple receptor-ligand interactions. The possibility of a tethering step, mediated by the engagement of stromal cell heparan sulphate with its ligands on the progenitor cells, preceding stable cell adhesion is discussed. The role of stromal cell heparan sulphate is likely to include cytokine presentation to progenitors as well as the tethering of progenitors to stroma. It is proposed that intracellular signals induced by progenitor cell adhesion to stroma act in association with cytokine induced signals to regulate progenitor cell proliferation and differentiation.
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Zinc-α2-glycoprotein (ZAG, also listed as AZGP1 in the MGI Database), a lipid-mobilising factor, has recently been suggested as a potential candidate in the modulation of body weight. We investigated the effect of increased adiposity on ZAG expression in adipose tissue and the liver and on plasma levels in obese ( ob/ob ) mice compared with lean siblings. The study also examined the effect of the pro-inflammatory cytokine tumour necrosis factor-α (TNFα) on ZAG expression in adipocytes. Zag mRNA levels were significantly reduced in subcutaneous (fourfold) and epididymal (eightfold) fat of ob/ob mice. Consistently, ZAG protein content was decreased in both fat depots of ob/ob mice. In the liver of obese animals, steatosis was accompanied by the fall of both Zag mRNA (twofold) and ZAG protein content (2.5-fold). Plasma ZAG levels were also decreased in obese mice. In addition, Zag mRNA was reduced in epididymal (fivefold) and retroperitoneal (fivefold) adipose tissue of obese ( fa/fa ) Zucker rats. In contrast to Zag expression, Tnfα mRNA levels were elevated in adipose tissue (twofold) and the liver (2.5-fold) of ob/ob mice. Treatment with TNFα reduced Zag gene expression in differentiated adipocytes, and this inhibition was chronic, occurring at 24 and 48 h following TNFα treatment. It is concluded that ZAG synthesis in adipose tissue and the liver is downregulated, as are its circulating levels, in ob/ob mice. The reduced ZAG production may advance the susceptibility to lipid accumulation in these tissues in obesity, and this could be at least in part attributable to the inhibitory effect of TNFα.
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Tumor necrosis factor-α (TNF; cachectin), a peptide secreted from stimulated macrophages, mediates some of the metabolic derangements in inflammatory and neoplastic disorders. To determine whether TNF is responsible for the changes in hypothalamic-pituitary-thyroid (HPT) function in nonthyroid illnesses, we administered synthetic human TNF to male Sprague-Dawley rats. The rats were given TNF or saline (control; both pair fed and nonpair fed) iv (six to eight per group). HPT function was tested 8 h after administration of 200 μg TNF/kg BW, 8 h after 5 days of 150 μg TNF/kg BW, and 8 h after a 3-day series of 50, 200, and 800 μg TNF/kg BW. The single injection of 200 μg TNF/kg significantly reduced (all P < 0.05) serum TSH, T4) free T4, T3, and hypothalamic TRH compared to the corresponding hormone levels in saline-injected control rats. Serum TSH and hypothalamic TRH recovered to normal levels after 5 days of 150 μg/kg TNF treatment. With the increasing daily doses of TNF, serum TSH and hypothalamic TRH fell significantly. Hepatic 5′ -deiodinase activity was reduced after 1 day of TNF treatment, but increased after the 3-day series of injections. TNF treatment reduced pituitary TSHβ mRNA, but did not affect a-subunit mRNA. TNF treatment also reduced thyroid I25I uptake and reduced thyroidal release of T4 and T3 in response to bovine TSH, but did not change the TSH response to TRH. TNF treatment reduced the binding of pituitary TSH to Concanavalin-A, indicating that it alters the glycosylation of TSH. The TSH with reduced affinity for this lectin had reduced biological activity when tested in cultured FRTL-5 rat thyroid cells. In vitro, TNF inhibited 125I uptake by cultured FRTL-5 rat thyroid cells and blocked the stimulation of [3H]thymidine uptake by these cells. The data indicate that TNF acts on the HPT axis at multiple levels and suggest that TNF is one of the mediators responsible for alterations in thyroid function tests in patients with nonthyroidal illnesses.
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Tumor necrosis factor-α decreases thyrotropin-induced 5′-deiodinase activity in FRTL-5 thyroid cells
Ongphiphadhanakul B, Fang SL, Tang K-T, Patwardhan NA, Braverman LE. Tumor necrosis factor-α decreases thyrotropin-induced 5′-deiodinase activity in FRTL-5 thyroid cells. Eur J Endocrinol 1994;130:502–7. ISSN 0804–4643 Tumor necrosis factor-α (TNF-α) exerts various effects on many cell types. Acute administration of TNF-α to rats decreases hepatic 5′-deiodinase activity (5′D-I) and TNF-α has been implicated in the pathogenesis of the low triiodothyronine syndrome in non-thyroidal illness in humans. The thyroid, liver and kidney are rich in 5′D-I. Unlike hepatic and renal 5′D-I, thyroid 5′D-I is regulated by thyrotropin. We have investigated the effects of TNF-α on 5D-I in FRTL-5 cells, a cultured rat thyroid follicular cell line. Tumor necrosis factor-α did not significantly affect basal 5′D-I but thyrotropin markedly increased 5′D-I (p < 0.001). This TSH-induced increase in 5′D-I was attenuated by TNF-α in a dose-dependent manner (p < 0.001). Enzyme kinetic analysis demonstrated that thyrotropin increased 5′D-I by increasing V max (p < 0.01) without significantly affecting K m . Likewise, TNF-α decreased the thyrotropin-induced 5′D-I by decreasing V max (p < 0.05) but not K m . The effect of TNF-α on thyrotropin-induced 5′D-I in FRTL-5 cells is probably mediated through post-thyrotropin-induced generation of cyclic adenosine monophosphate (cAMP) because TNF-α inhibited both dibutyryl cAMP (p < 0.001) and forskolin (p < 0.001)-induced increases in 5′D-I without affecting cAMP generation stimulated by thyrotropin. In conclusion, we have demonstrated that TNF-α inhibits thyrotropininduced 5′D-I activity in FRTL-5 cells by pathways distal to the generation of cAMP and that TNF-α may play a role in the modulation of the production of triiodothyronine by the thyroid gland. Furthermore, the increase in TNF-α observed in patients with the euthyroid sick syndrome may contribute to the low serum triiodothyronine observed in these patients, not only by inhibiting peripheral generation of triiodothyronine from thyroxine but also by decreasing thyroidal generation and subsequent secretion of triiodothyronine. Lewis E Braverman, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA 01655, USA
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The hypophysectomized rat has been used as a model to study the effects of growth hormone deficiency on bone. Here, we have investigated the influence of growth hormone administration to hypophysectomized rats (HX) for 6 wk on accumulation of triglycerides in bone marrow and on the differentiation of primary marrow stromal cells into adipocytes under in vitro conditions. We found that hypophysectomy significantly increased triglyceride concentration in bone marrow, which was attenuated by growth hormone administration. Primary bone marrow stromal cells derived from HX rats also had more adipocytes at confluence compared with growth hormone-treated hypophysectomized (GH) rats. When stimulated with 3-isobutyl-1-methylxanthine plus dexamethasone (IBMX-Dex), preadipocyte colony counts increased more significantly in GH rats. Markers of adipocyte differentiation were higher in HX than in control or GH rats at confluence. However, after stimulation with IBMX-Dex, increased expression of markers was seen in GH compared with HX rats. In conclusion, growth hormone administration to hypophysectomized rats attenuated triglyceride accumulation in bone marrow and inhibited the differentiation of stromal cells into adipocytes in vitro.
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