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141.
142.
Induction of IL-5 expression by IL-2 is resistant to the immunosuppressive agents cyclosporin A and rapamycin 总被引:1,自引:0,他引:1
T cell cytokine expression may be induced by the cytokine IL-2 or via the
TCR complex. The comparative effects of cytokine- and TCR-mediated
signalling on the induction of human IL-5 mRNA were examined. Cytokine mRNA
expression was analysed by RT-PCR in fresh peripheral blood mononuclear
cells (PBMC) from normal individuals and in populations of activated T
lymphocytes, derived from phytohaemagglutinin (PHA)- stimulated PBMC. rIL-2
induced IL-5 expression in PBMC, the kinetics of which were similar to the
effects of PHA. rIL-4 induced IL-5 mRNA expression in activated T
lymphocytes. IL-5 expression induced by either IL-2 or PHA was completely
abolished by the protein synthesis inhibitor cycloheximide. rIL-2-induced
IL-5 expression was resistant to cyclosporin A (CsA), whereas IL-5
expression elicited by PHA was inhibited by CsA, at doses as low as 10
ng/ml. Rapamycin (RAP) had no effect on rIL-2-stimulated IL-5 expression,
but suppressed IL-5 expression induced by PHA. The inhibitory effect of RAP
on PHA-induced IL-5 expression was more apparent at 12 and 24 h after
stimulation than at earlier times. The resistance of IL-2 receptor (IL-2R)
signalling to CsA and RAP indicates that the IL-2R and the TCR are
associated with different pathways regulating IL-5 expression.
相似文献
143.
Krimer LS; Herman MM; Saunders RC; Boyd JC; Hyde TM; Carter JM; Kleinman JE; Weinberger DR 《Cerebral cortex (New York, N.Y. : 1991)》1997,7(8):732-739
The entorhinal cortex (ERC) has been implicated in schizophrenia by a
number of studies. There is anatomical observation of neuronal heterotopias
in the rostral ERC, which is consistent with a hypothesis of
neurodevelopmental abnormalities in this disease. In view of the
significant cytoarchitectonic variation of the ERC throughout its
rostro-caudal extent, we performed a detailed subareal analysis of the
rostral two-thirds of the entorhinal cortex (ERCr) in 14 postmortem
schizophrenic brains and 14 matched controls (mean ages of 48 and 47
respectively). This systematic evaluation included both a qualitative
microscopic analysis of morphogenetic anomalies that would be consistent
with neurodevelopmental pathology and quantitative measurements of total
neuronal number, average neuronal density, laminar volume and laminar depth
from the cortical surface in cytoarchitectonically matched subareas of
schizophrenic and control brains. Parcellation of the entire ERC on the
basis of cytoarchitectonic criteria identified five distinct regions,
similar to those described in the macaque, except that in the human brain
three of the regions were further divisible into two or three subareas,
yielding nine distinct cellular compartments. Five rostral areas, prorhinal
(Pr), lateral (28L), intermediate rostral and caudal (281r and 281c), and
sulcal (28S), comprise the ERCr. Gross and microscopic examination of these
subdivisions throughout the ERCr failed to reveal laminar disorganization
in any of the schizophrenic brains. The brains also did not differ
significantly with respect to total neuronal number, total volume and
neuronal density per laminar and subareal subdivision, or laminar thickness
per entorhinal subarea. However, neuronal number and density were reduced
by 12-18% in Pr and 28L, suggesting that mild quantitative abnormalities
may exist in the ERCr and might possibly be revealed in a larger sample of
schizophrenic brains. We have failed to confirm previous reports of laminar
disorganization in the ERCr in brains of patients with schizophrenia; to
the extent that this region is implicated in schizophrenia, the structural
changes are likely to consist of more subtle cellular disturbances.
相似文献
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Trimetrexate (TMTX) is an anticancer drug with potential advantages over the more commonly used antifolate, methotrexate (MTX); however, its use has been limited by severe myelosuppression. Retroviral vectors containing mutant dihydrofolate reductase (DHFR) genes have been used to protect bone marrow cells from MTX, suggesting a similar approach could be used for TMTX. We first screened six variants of human DHFR to determine which allowed maximal TMTX resistance in fibroblasts. A variant enzyme containing a Leu-to-Tyr mutation in the 22nd codon (L22Y) was best, allowing a 100-fold increase in resistance over controls. Murine hematopoietic progenitor cells transduced with an L22Y- containing retroviral vector also showed high-level TMTX resistance in vitro. Mice reconstituted with L22Y-transduced bone marrow cells were challenged with a 5-day course of TMTX to determine whether hematopoiesis could be protected in vivo. Transfer of the L22Y vector resulted in consistent protection from TMTX-induced neutropenia and reticulocytopenia at levels that correlated with the proviral copy number in circulating leukocytes. We conclude that the L22Y vector is highly effective in protecting hematopoiesis from TMTX toxicity and may provide a means for increasing the therapeutic utility of TMTX in certain cancers. 相似文献
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