Diminished heat-shock protein synthesis following mitogen stimulation of lymphocytes from aged donors

Faassen, Anne E.; O’Leary, James J.; Rodysill, Kirk J.; Bergh, Nona; Hallgren, Helen M.

doi:10.1016/0014-4827(89)90393-5

Cited by 62 publications

(14 citation statements)

References 26 publications

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“…Age-associated inactivation of proteosome function has been independently reported and attributed to the effects oxidative damage, which can be partly prevented by hsp90 (118). Hsp90 levels are themselves decreased with age in PHA-stimulated T cells (196). Whisler et al (187) also found reduced NF-kappa B in some elderly human donors´ stimulated T cells, but they did not find a correlation with depressed IL 2 production (unlike their findings with NF-AT, see above).…”

Section: Cytokine Production and Responsementioning

confidence: 90%

“…Some recent data implicate hsp70 as a protector against apoptosis (652), others show that overexpression of transfected hsp70 enhances AICD in T cells (653). The expression not only of the hsp70 family, but also hsp90 family stress proteins has been reported to be reduced after PHA stimulation of aged T cells directly ex vivo, suggesting that results with cultured cells are relevant to the in vivo situation (196). There is now some evidence that hsp90 plays a part in CD28-mediated T cell activation (654), suggesting that reduction of hsp90 might further reduce the already compromised function of CD28 in aging and help to explain lack of function even of the CD28 still expressed on old (mouse) cells (see section 4.2.1).…”

Section: Stressmentioning

confidence: 99%

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T cells and aging update February 1999

Pawelec¹

1999

Front Biosci

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T cell immunosenescence 218effects of dysregulated immune responses in the elderly by supplementation or other approaches may result in an enhancement of their quality of life, and significant reductions in the cost of medical care in old age. FACTORS CONTRIBUTING TO IMMUNO-SENESCENCE HematopoiesisDysregulated hematopoiesis is seen in elderly individuals, raising the possibility that this could contribute to altered immune function in the aged. Hematopoiesis in man may be compromised because of a severely reduced capacity to produce colony stimulating factors (44) and increased production of pro-inflammatory factors such as IL 6 (45), because lower numbers of progenitor cells are present in the BM (46) and because of an age-related decline in proliferative potential of putative haematopoietic stem cells (HSC) (47). In mice, the repopulating potential of murine fetal liver-derived HSC is higher than that of adult BM-derived stem cells (48), suggesting possible aging of the HSC themselves. Normal cells with shorter telomeres possess less remaining replicative capacity than those with longer telomeres (see section 5.2). Accordingly, HSC from adult BM were found to have shorter telomeres than fetal liver-derived or umbilical cord-derived stem cells, consistent with aging of HSC (49). Telomere lengths decreased on culture despite low level expression of telomerase in these cells (50,51), although the rate of basepair loss per population doubling of cells in culture was lower during the first two weeks, when telomerase was upregulated, than in the next two, when it was downregulated (52). The telomerase expressed is therefore functionally active but may not be able to completely maintain telomere length in aging HSC cells. True embryonic stem cells (ESC), on the other hand, which may really be immortal, do retain high levels of telomerase activity (53). On the other hand, ESC from telomerase-knockout mice show gradual telomere shortening over many population doublings (PD) resulting in slowing and eventual cessation of growth (54). Certain animals which do not downregulate telomerase manifest a permanent growth phase and little or no senescence (55,56).

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Section: Cytokine Production and Responsementioning

confidence: 90%

Section: Stressmentioning

confidence: 99%

T cells and aging update February 1999

Pawelec¹

1999

Front Biosci

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“…None of the cited studies specifically addresses the basal synthesis of HSP70 even though few observations [5,6] show detectable HSP70 concentrations in different unstressed mammalian cells and tissues as well as in insects, without age-related changes.…”

Section: Discussionmentioning

confidence: 99%

“…A blunted HSP synthesis has been described in aging as a response to acute stress, but age-dependent modifications of HSP70 basal expression have not been specifically addressed so far, and reports describe unchanged [5,6] or increased [7] HSP70 basal levels, often undetectable in unstimulated conditions [8][9][10][11][12].…”

Section: Introductionmentioning

confidence: 99%

Basal Synthesis of Heat Shock Protein 70 Increases with Age in Rat Kidneys

Maiello

Boeri²,

Sampietro³

et al. 1997

Gerontology

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The heat shock protein (HSP) system is a mechanism of cell defense induced by stress, constitutively expressed during basal conditions and essential to the maintenance of cellular integrity. Acutely induced HSP synthesis decreases with aging, but the effect of age on the basal expression of HSP70 has not been specifically addressed so far. The aim of this work is to study the age-dependent basal concentrations of HSP70 mRNA in rat kidneys. In 8 young (2–3 months), 6 adult (6–11 months) and 6 old male Wistar rats (22–27 months), steady-state concentrations of HSP70 and γ-actin mRNA and of rRNA were measured. Pentosidine was measured by HPLC. The basal, unstimulated HSP70 mRNA is increased in young and old rats compared with adult subjects [young: 182% of adult levels (100–299), old: 167% of adults (142–209); p < 0.005]. The amount of pentosidine increases with age (young: 0.6 ± 0.1; adult: 1.65 ± 0.15; old: 2.3 ± 0.3 pmol/mg of protein; p < 0.0001). It seems likely that different mechanisms are responsible for the increased HSP70 basal synthesis in both the young and old animals. The prevalence of anabolic activity can trigger the increased basal production of HSP70 in young rats. The accumulation of posttranslational modified proteins, documented by pentosidine, can chronically enhance HSP70 synthesis in aged animals. The suppression of the synthesis of other proteins accompanying HSP-selective production might contribute to the impairment of specific cell functions in aging.

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“…Diminished Hsp90 messenger RNA (mRNA) and protein synthesis following mitogen stimulation of lymphocytes with interleukin-2 (IL-2) has been measured in aged donors of T lymphocytes (7), and tissue from aged animals and blood from elderly humans show reduced production of stress proteins, including Hsp90, following thermal stress (4,8).…”

mentioning

confidence: 99%

Hsp90 mediates insulin‐like growth factor 1 and interleukin‐1β signaling in an age‐dependent manner in equine articular chondrocytes

Boehm¹,

Seth²,

Mayr³

et al. 2007

Arthritis & Rheumatism

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Objective. Many metabolic processes in chondrocytes thought to contribute to age-related changes in the extracellular matrix are influenced by known roles of Hsp90. Age-related decreases in the level of Hsp90 have been documented in numerous cell types and could contribute to cartilage degeneration. The aim of this study was to investigate the roles of age and Hsp90 in insulin-like growth factor 1 (IGF-1) and interleukin-1␤ (IL-1␤) signaling in chondrocytes.Methods. Levels of Hsp90 messenger RNA (mRNA) and protein, with respect to age, were determined by quantitative real-time polymerase chain reaction (PCR) and Western blot analysis, respectively. The Hsp90 inhibitor geldanamycin (50 nM, 100 nM, or 500 nM) was used to assess age-related responses to Hsp90 with concurrent IGF-1 or IL-1␤ stimulation of chondrocytes. Quantitative real-time PCR was used to measure COL2A1 and matrix metalloproteinase 13 (MMP13) gene expression; Western blot analysis was performed to determine the phosphorylation status of p42/44 and Akt/protein kinase B.Results. The effects of Hsp90 inhibition with geldanamycin were concentration dependent. Inhibition of Hsp90 with 100 nM or 500 nM geldanamycin blocked IGF-1-induced cell proliferation, Akt and p42/44 activation, and COL2A1 expression. Basal and IL-1␤-induced up-regulation of MMP13 mRNA was blocked by all concentrations of geldanamycin tested. Gain-offunction assays with Hsp90 resulted in increased expression of MMP13 mRNA.Conclusion. These results suggest that Hsp90 is involved in opposing signaling pathways of cartilage homeostasis, and that catabolic responses are more sensitive to Hsp90 inhibition than are anabolic responses. Further studies are needed to determine the role of Hsp90 inhibition in osteoarthritis in order to assess its potential as a therapeutic target.

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Diminished heat-shock protein synthesis following mitogen stimulation of lymphocytes from aged donors

Cited by 62 publications

References 26 publications

T cells and aging update February 1999

T cells and aging update February 1999

Basal Synthesis of Heat Shock Protein 70 Increases with Age in Rat Kidneys

Hsp90 mediates insulin‐like growth factor 1 and interleukin‐1β signaling in an age‐dependent manner in equine articular chondrocytes

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