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1.
Childhood exposure to ambient polycyclic aromatic hydrocarbons is linked to epigenetic modifications and impaired systemic immunity in T cells 下载免费PDF全文
K. M. Hew A. I. Walker A. Kohli M. Garcia A. Syed C. McDonald‐Hyman E. M. Noth J. K. Mann B. Pratt J. Balmes S. Katharine Hammond K. C. Nadeau 《Clinical and experimental allergy》2015,45(1):238-248
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Caroline Marie Jean‐Luc Ravanat Carine Badouard Marie Marques Franck Balducci Anne Maître 《Environmental and molecular mutagenesis》2009,50(2):88-95
Polycyclic aromatic hydrocarbons (PAH) are ubiquitous occupational and environmental pollutants and the urinary excretion of 1‐hydroxypyrene (1‐OHP) is classically measured for the determination of PAH exposure internal dose. Some of PAH are tumorigenic due to their metabolites ability to generate DNA adducts and oxidative DNA damage through the production of reactive oxygen species during metabolism. 8‐hydroxy‐7,8‐dihydro‐2′‐deoxyguanosine (8‐OHdGuo) is one of the major oxidative DNA lesions and its use as a potential biomarker of genotoxic PAH occupational exposure should be evaluated. Indeed conflicting results are frequently reported in occupational studies in terms of correlation between 8‐OHdGuo urinary levels and PAH exposure. The aim of our study was therefore to determine the potential for PAH occupational exposure to increase urinary oxidative DNA damage. The population consisted of 68 male workers employed in silicon production. The urinary concentrations of 8‐OHdGuo and its homologue in RNA, 8‐hydroxy‐7,8‐dihydroguanosine (8‐OHGuo) were determined using high performance liquid chromatography (HPLC) coupled to tandem mass spectrometry, whereas those of 1‐OHP were measured using HPLC with fluorescence detection. Individual variation rates were calculated on a working day and a working week. The results indicated that, while 1‐OHP levels strongly increased on a working day and even more on a working week, 8‐OHdGuo and 8‐OHGuo urinary levels did not show similar significant increases. Moreover, no correlation between 1‐OHP and oxidative DNA and RNA lesions was found. Consequently, urinary 8‐OHdGuo and 8‐OHGuo did not seem to be relevant biomarkers of genotoxic PAH exposure in the case of the silicon plant studied. Environ. Mol. Mutagen., 2009. © 2008 Wiley‐Liss, Inc. 相似文献
3.
Urinary 8‐hydroxydeoxyguanosine (8‐OHdG) is considered a noninvasive marker for oxidative stress and also a marker of carcinogenic potential for compounds such as polycyclic aromatic hydrocarbons (PAHs). Although human studies have investigated urinary 8‐OHdG concentrations in PAH‐exposed workers and the general population, the background level and excretion kinetics of urinary 8‐OHdG in humans remain unclear. Two feeding experiments (consumption of barbecued meat of 15 and 30 g/kg for Experiments 1 and 2, respectively) were conducted to examine the excretion characteristics of urinary 8‐OHdG. All urine voided over 7 days was collected, but only first morning (~8 A.M .) and last afternoon (~5 P.M .) samples were analyzed for 8‐OHdG. Mean background urinary 8‐OHdG concentration was 4.76 μg/g creatinine. Statistically significant increases (P < 0.05) in urinary 8‐OHdG concentration were observed on the afternoon of the 3rd and 2nd days after barbecued meat consumption for Experiments 1 and 2, respectively. A pattern of diurnal fluctuation (P < 0.05) in 8‐OHdG excretion rate was evident, in that the excretion of 8‐OHdG was faster during the night than during the day. Additionally, significant (P < 0.05) and strong (r > 0.6) correlations were found between urinary 8‐OHdG measured 2–3 days after exposure to barbecued meat, and 1‐hydroxypyrene (1‐OHP) and 3‐hydroxy‐benzo[a]pyrene (3‐OHBaP) concentrations measured within a half day after such exposure. The current results demonstrate a lag in excretion of urinary 8‐OHdG relative to 1‐OHP and 3‐PHBaP after dietary PAH exposure. These relationships highlight the importance of sampling time when assessing PAH‐related DNA lesions through urinary 8‐OHdG. Environ. Mol. Mutagen. 2010. © 2009 Wiley‐Liss, Inc. 相似文献
4.
Expression of Natural Cytotoxicity Receptors on and Intracellular Cytokine Production by NK Cells in Women with Gestational Diabetes Mellitus 下载免费PDF全文
Hitomi Chiba Atsushi Fukui Kohei Fuchinoue Ayano Funamizu Kanji Tanaka Hideki Mizunuma 《American journal of reproductive immunology (New York, N.Y. : 1989)》2016,75(5):529-538
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Urinary excretion rates of PGE2 and PGF2α were measured radioimmunologically in four different groups of unanaesthetized rats: water diuretic rats (I), rats with free access to water (II), water deprived rats (III) and 1.5% saline-loaded rats (IV). The animals were decapitated when steady states of urine formation were ascertained for three to six spontaneously delivered urine portions. Plasma vasopressin was measured radioimmunologically and urea, sodium, potassium concentrations and osmolalities of papillary fluids and of bladder urines were determined. Group means of urinary prostaglandin excretion, papillary urea concentration and logarithmic-transformed plasma vasopressin values vary in parallel for three of the groups (I, II and III) but a dissociation of the effects of papillary urea and vasopressin on the prostaglandin excretion was obtained for group IV. Statistical analyses indicated that the differences in prostaglandin excretion rates between group I and the three other groups are accounted for by the combined effects of vasopressin and papillary urea. The results support the hypothesis that vasopressin stimulates release of arachidonic acid in the papilla and that urea inhibits the trapping of this prostaglandin precursor in cellular lipids. The ratio of urinary PGF2α to PGE2 varied greatly between groups but no consistent dependency on the measured parameters was found. 相似文献
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TSLP production by dendritic cells is modulated by IL‐1β and components of the endoplasmic reticulum stress response 下载免费PDF全文
Matthew J. Elder Steven J. Webster David L. Williams J. S. Hill Gaston Jane C. Goodall 《European journal of immunology》2016,46(2):455-463
Thymic stromal lymphopoietin (TSLP) produced by epithelial cells acts on dendritic cells (DCs) to drive differentiation of TH2‐cells, and is therefore important in allergic disease pathogenesis. However, DCs themselves make significant amounts of TSLP in response to microbial products, but little is known about the key downstream signals that induce and modulate this TSLP secretion from human DCs. We show that human monocyte derived DC (mDC) secretion of TSLP in response to Candida albicans and β‐glucans requires dectin‐1, Syk, NF‐κB, and p38 MAPK signaling. In addition, TSLP production by mDCs is greatly enhanced by IL‐1β, but not TNF‐α, in contrast to epithelial cells. Furthermore, TSLP secretion is significantly increased by signals emanating from the endoplasmic reticulum (ER) stress response, specifically the unfolded protein response sensors, inositol‐requiring transmembrane kinase/endonuclease 1 and protein kinase R‐like ER kinase, which are activated by dectin‐1 stimulation. Thus, TSLP production by mDCs requires the integration of signals from dectin‐1, the IL‐1 receptor, and ER stress signaling pathways. Autocrine TSLP production is likely to play a role in mDC‐controlled immune responses at sites removed from epithelial cell production of the cytokine, such as lymphoid tissue. 相似文献
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The effect of a constant infusion of furosemide (130 μg/min i.v. for 60 min, n = 8) was studied on urinary excretion of water, electrolytes and immunoreactive prostaglandin E2 (iPGE2) and iPGF2α in chloralose-urethane anesthetized rabbits. During the furosemide infusion sodium and water excretion increased tenfold and the excretion of potassium and iPGE2 two to three times. The excretion of iPGF2α (0.06 ± 0.03 μg/min/100 g kidney weight) was not significantly changed during the furosemide infusion but increased markedly after the infusion and reached a maximum (1.0 ± 0.6 μg/min/100 g) 30 to 45 min later, while the small increase in iPGE2 excretion at this time could be attributed to cross-reaction with PGF2α The results indicate that PGE2 might possibly be involved directly in the action of furosemide, while PGF2α might participate in sodium and water conserving mechanisms in the rabbit kidney, activated by the drug induced diuresis. 相似文献
10.
《Immunology》2017,151(3):340-348
T regulatory (Treg) cells are critical for preventing autoimmunity and suppressing immune responses during cancer and chronic infection. However, the role of Treg cells in the generation of vaccine‐induced immune memory remains ill‐defined. Using the mouse model of lymphocytic choriomeningitis virus (LCMV) infection, we demonstrate that transient absence of Treg cells during effector to memory CD8 T‐cell transition results in a permanent impairment in the maintenance, function and recall capacity of CD8 T cells. Memory CD8 T cells in mice that were transiently depleted of Treg cells exhibited defective up‐regulation of memory markers with a significant decrease in polyfunctionality. However, Treg‐depleted mice showed no significant change in CD4 T‐cell responses, and antibody levels relative to control. Altogether, this study evaluates the role of Treg cells in the formation of immune memory and demonstrates an important role for Treg cells in promoting memory CD8 T‐cell differentiation and vaccine‐induced immune protection against intracellular pathogens. 相似文献
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Transcriptional regulation of Hb‐α and Hb‐β through nuclear factor E2‐related factor‐2 (Nrf2) activation in human vaginal cells: A novel mechanism of cellular adaptability to oxidative stress 下载免费PDF全文
Debarchana Saha Swanand Koli Kudumula Venkata Rami Reddy 《American journal of reproductive immunology (New York, N.Y. : 1989)》2017,77(6)
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Hypoxic inactivation of glycogen synthase kinase‐3β promotes gastric tumor growth and angiogenesis by facilitating hypoxia‐inducible factor‐1 signaling 下载免费PDF全文
Young San Ko Sung Jin Cho Jinju Park Yiseul Choi Jae‐Seon Lee Hong‐Duk Youn Woo Ho Kim Min A Kim Jong‐Wan Park Byung Lan Lee 《APMIS : acta pathologica, microbiologica, et immunologica Scandinavica》2016,124(9):748-756
Since the molecular mechanism of hypoxic adaptation in cancer cells is cell‐type specific, we investigated whether glycogen synthase kinase‐3β (GSK‐3β) activation is involved in hypoxia‐induced gastric tumor promotion. Stable gastric cancer cell lines (SNU‐638, SNU‐484, MKN1, and MKN45) were cultured under hypoxic conditions. Cells overexpressing wild‐type GSK‐3β (WT‐GSK‐3β) or kinase‐dead mutant of GSK‐3β (KD‐GSK‐3β) were generated and used for cell culture and animal studies. In cell culture experiments, hypoxia decreased GSK‐3β activation in gastric cancer cells. Cell viability and the expressions of HIF‐1α protein and VEGF mRNA in gastric cancer cells were higher in KD‐GSK‐3β transfectants than in WT‐GSK‐3β transfectants under hypoxic conditions, but not under normoxic conditions. Gastric cancer xenografts showed that tumor growth, microvessel area, HIF‐1α activation, and VEGF expression were higher in KD‐GSK‐3β tumors than in WT‐GSK‐3β tumors in vivo. In addition, the expression of hypoxia‐induced HIF‐1α protein was regulated by GSK‐3β at the translational level. Our data suggest that GSK‐3β is involved in hypoxic adaptation of gastric cancer cells as an inhibitory upstream regulator of the HIF‐1α/VEGF signaling pathway. 相似文献
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Pro‐migratory and TGF‐β‐activating functions of αvβ6 integrin in pancreatic cancer are differentially regulated via an Eps8‐dependent GTPase switch 下载免费PDF全文
Jo Tod Christopher J Hanley Mark R Morgan Marta Rucka Toby Mellows Maria‐Antoinette Lopez Philip Kiely Karwan A Moutasim Steven J Frampton Durgagauri Sabnis David R Fine Colin Johnson John F Marshall Giorgio Scita Gareth J Thomas 《The Journal of pathology》2017,243(1):37-50
The integrin αvβ6 is up‐regulated in numerous carcinomas, where expression commonly correlates with poor prognosis. αvβ6 promotes tumour invasion, partly through regulation of proteases and cell migration, and is also the principal mechanism by which epithelial cells activate TGF‐β1; this latter function complicates therapeutic targeting of αvβ6, since TGF‐β1 has both tumour‐promoting and ‐suppressive effects. It is unclear how these different αvβ6 functions are linked; both require actin cytoskeletal reorganization, and it is suggested that tractive forces generated during cell migration activate TGF‐β1 by exerting mechanical tension on the ECM‐bound latent complex. We examined the functional relationship between cell invasion and TGF‐β1 activation in pancreatic ductal adenocarcinoma (PDAC) cells, and confirmed that both processes are αvβ6‐dependent. Surprisingly, we found that cellular functions could be biased towards either motility or TGF‐β1 activation depending on the presence or absence of epidermal growth factor receptor pathway substrate 8 (Eps8), a regulator of actin remodelling, endocytosis, and GTPase activation. Similar to αvβ6, we found that Eps8 was up‐regulated in >70% of PDACs. In complex with Abi1/Sos1, Eps8 regulated αvβ6‐dependent cell migration through activation of Rac1. Down‐regulation of Eps8, Sos1 or Rac1 suppressed cell movement, while simultaneously increasing αvβ6‐dependent TGF‐β1 activation. This latter effect was modulated through increased cell tension, regulated by Rho activation. Thus, the Eps8/Abi1/Sos1 tricomplex acts as a key molecular switch altering the balance between Rac1 and Rho activation; its presence or absence in PDAC cells modulates αvβ6‐dependent functions, resulting in a pro‐migratory (Rac1‐dependent) or a pro‐TGF‐β1 activation (Rho‐dependent) functional phenotype, respectively. © 2017 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland. 相似文献
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ERNST OLIW INGER LUNDN BIRGITTA SJ
QUIST ERIK NGGRD 《Acta physiologica (Oxford, England)》1979,105(3):359-366
The occurrence of 6-keto-prostaglandin Flα (6-keto-PGF1α) was demonstrated in rabbit kidney medulla and cortex by mass-spectrometry. The post-mortem accumulation of 6-keto-PGF1α was studied by mass-fragmentography in regions of the rabbit kidney using (3,3,4,4,-2H4) 6-keto-PGFlα as an internal standard. The cortex contained 1.4 + 0.3 μMg/g, the medulla 2.1 ± 0.6 μg/g and the papilla 3.7 ± 0.7 (S.E.) μg/g. The accumulation of 6-keto-PGF1α is thus about 5 fold higher in the cortex than reported for PGE2 and PGF2α, whereas accumulation of PGE2 and PGF2α dominates over 6-keto-PGFlα in the medulla and the papilla. The occurrence of 6-keto-PGFlα in rabbit urine was demonstrated by mass-fragmentography. On a low salt diet unanesthetized, female rabbits (n = 6) excreted Na+ 0.09 ± 0.01 (S.E.) mmol/day, 6-keto-PGFlα 11.8 ± 2.2 μg/day and immunoreactive PGF2α (iPGF2α) 2.0 ± 0.6 μg/day. Two days treatment with acetylsalicylic acid (30 mg/kgx 2) reduced urinary excretion of 6-keto-PGFlα and iPGF2α by 71 and 85%, respectively (both p < 0.05), but sodium excretion was unchanged. On the same diet supplemented with NaCl, the rabbits excreted Na+ 27.5 ± 3.4 mmol/day (p < 0,05), 6-keto-PGFlα 13.3 ± 4.6 μg/day (p > 0.05) and iPGF2α 0.63 ± 0.10 μg/day (p < 0.05). 6-keto-PGFlα is a major metabolite of prostacyclin (PGI2). The occurrence of 6-keto-PGFlα in kidney and urine indicates a considerable synthesis of PGI2 in the kidney. The data on urinary PG excretion indicate that intrarenal synthesis of PGI2, in contrast to PGF2α, is not influenced by dietary variations in NaCl. 相似文献
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Aim: Several studies have shown that a variety of peptides and cytokines are involved in ovarian regulatory mechanisms; however, their exact function is still unclear. In this work we study whether the administration of peptide α‐melanotropin and the cytokines interleukin‐1β (IL‐1β) and tumour necrosis factor‐α (TNF‐α) on their own modify the release of progesterone in cultured granulosa cells (GC) from pro‐oestrous rats. We also investigate an interaction between these cytokines and α‐melanotropin in the modulation of progesterone secretion. Methods: Granulosa cells were collected from the ovaries of female Wistar rats and cultured for up to 24 h in the presence of different concentrations of α‐melanotropin, cytokines or a combination of both. Progesterone concentration was measured by radioimmunoassay. Results: The addition of α‐melanotropin in a dose of 0.01 and 0.1 mm had no effect on progesterone release, whereas a dose of 1 mm significantly increased progesterone release (P < 0.01) compared with the control culture. Progesterone release was not modified when different concentrations of interleukin‐1β or TNF‐α were added to the cell cultures. However, when interleukin‐1β or TNF‐α were added simultaneously with 1 μm α‐melanotropin, a significant reduction (P < 0.01 for interleukin‐1β and P < 0.05 for TNF‐α) of the steroid release was found with respect to the α‐melanotropin‐treated group. Conclusions: These results lead us to suggest that, although α‐melanotropin stimulates progesterone release in pre‐ovulatory GC, this effect is blocked by the presence of interleukin‐1β or TNF‐α. 相似文献
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The Nlrp3 inflammasome,IL‐1β, and neutrophil recruitment are required for susceptibility to a nonhealing strain of Leishmania major in C57BL/6 mice 下载免费PDF全文
Melanie Charmoy Benjamin P. Hurrell Audrey Romano Sang Hun Lee Flavia Ribeiro‐Gomes Nicolas Riteau Katrin Mayer‐Barber Fabienne Tacchini‐Cottier David L. Sacks 《European journal of immunology》2016,46(4):897-911
Infection of C57BL/6 mice with most Leishmania major strains results in a healing lesion and clearance of parasites from the skin. Infection of C57BL/6 mice with the L. major Seidman strain (LmSd), isolated from a patient with chronic lesions, despite eliciting a strong Th1 response, results in a nonhealing lesion, poor parasite clearance, and complete destruction of the ear dermis. We show here that in comparison to a healing strain, LmSd elicited early upregulation of IL‐1β mRNA and IL‐1β‐producing dermal cells and prominent neutrophil recruitment to the infected skin. Mice deficient in Nlrp3, apoptosis‐associated speck‐like protein containing a caspase recruitment domain, or caspase‐1/11, or lacking IL‐1β or IL‐1 receptor signaling, developed healing lesions and cleared LmSd from the infection site. Mice resistant to LmSd had a stronger antigen‐specific Th1 response. The possibility that IL‐1β might act through neutrophil recruitment to locally suppress immunity was supported by the healing observed in neutropenic Genista mice. Secretion of mature IL‐1β by LmSd‐infected macrophages in vitro was dependent on activation of the Nlrp3 inflammasome and caspase‐1. These data reveal that Nlrp3 inflammasome‐dependent IL‐1β, associated with localized neutrophil recruitment, plays a crucial role in the development of a nonhealing form of cutaneous leishmaniasis in conventionally resistant mice. 相似文献
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Interferon‐γ enhances both the anti‐bacterial and the pro‐inflammatory response of human mast cells to Staphylococcus aureus 下载免费PDF全文
Emily J. Swindle Jared M. Brown Madeleine Rådinger Frank R. DeLeo Dean D. Metcalfe 《Immunology》2015,146(3):470-485
Human mast cells (huMCs) are involved in both innate and adaptive immune responses where they release mediators including amines, reactive oxygen species (ROS), eicosanoids and cytokines. We have reported that interferon‐γ (IFN‐γ) enhances FcγR‐dependent ROS production. The aim of this study was to extend these observations by investigating the effect of IFN‐γ on the biological responses of huMCs to Staphylococcus aureus. We found that exposure of huMCs to S. aureus generated intracellular and extracellular ROS, which were enhanced in the presence of IFN‐γ. IFN‐γ also promoted bacteria killing, β‐hexosaminidase release and eicosanoid production. Interferon‐γ similarly increased expression of mRNAs encoding CCL1 to CCL4, granulocyte–macrophage colony‐stimulating factor (GM‐CSF), tumour necrosis factor‐α and CXCL8 in S. aureus‐stimulated huMCs. The ability of IFN‐γ to increase CXCL8 and GM‐CSF protein levels was confirmed by ELISA. Fibronectin or a β1 integrin blocking antibody completely abrogated IFN‐γ‐dependent S. aureus binding and reduced S. aureus‐dependent CXCL8 secretion. These data demonstrate that IFN‐γ primes huMCs for enhanced anti‐bacterial and pro‐inflammatory responses to S. aureus, partially mediated by β1 integrin. 相似文献
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NLRP3 inflammasome mediates interleukin‐1β production in immune cells in response to Acinetobacter baumannii and contributes to pulmonary inflammation in mice 下载免费PDF全文
《Immunology》2017,150(4):495-505
Acinetobacter baumannii is a multi‐drug resistant, Gram‐negative bacteria and infection with this organism is one of the major causes of mortality in intensive care units. Inflammasomes are multiprotein oligomers that include caspase‐1, and their activation is required for maturation of interleukin‐1β (IL‐1β). Inflammasome signalling is involved in host defences against various microbial infections, but the precise mechanism by which A. baumannii activates inflammasomes and the roles of relevant signals in host defence against pulmonary A. baumannii infection are unknown. Our results showed that NLRP3, ASC and caspase‐1, but not NLRC4, are required for A. baumannii‐induced production of IL‐1β in macrophages. An inhibitor assay revealed that various pathways, including P2X7R, K+ efflux, reactive oxygen species production and release of cathepsins, are involved in IL‐1β production in macrophages in response to A. baumannii. Interleukin‐1β production in bronchoalveolar lavage (BAL) fluid was impaired in NLRP3‐deficient and caspase‐1/11‐deficient mice infected with A. baumannii, compared with that in wild‐type (WT) mice. However, the bacterial loads in BAL fluid and lungs were comparable between WT and NLRP3‐deficient or caspase‐1/11‐deficient mice. The severity of lung pathology was reduced in NLRP3‐ deficient, caspase‐1/11‐ deficient and IL‐1‐receptor‐deficient mice, although the recruitment of immune cells and production of inflammatory cytokines and chemokines were not altered in these mice. These findings indicate that A. baumannii leads to the activation of NLRP3 inflammasome, which mediates IL‐1β production and lung pathology. 相似文献
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Gillespie GM Pinheiro S Sayeid-Al-Jamee M Alabi A Kaye S Sabally S Sarge-Njie R Njai H Joof K Jaye A Whittle H Rowland-Jones S Dorrell L 《European journal of immunology》2005,35(5):1445-1453
The mechanisms underlying the relatively slow progression of human immunodeficiency virus type 2 (HIV-2) compared with HIV-1 infection are undefined and could be a result of more effective immune responses. We used HIV-2 and HIV-1 IFN-gamma enzyme-linked immunospot assays to evaluate CD8(+) T cell responses in antiretroviral-naive HIV-2- ('HIV-2(+)') and HIV-1-infected ('HIV-1(+)') individuals. Gag-specific responses were detected in the majority of HIV-2(+) and HIV-1(+) subjects. Overlapping gag peptide analysis indicated a significantly greater magnitude and breadth of responses in the HIV-1(+) cohort, and this difference was attributable to low responses in HIV-2(+) subjects with undetectable viral load (medians 2107 and 512 spot-forming units per 10(6) PBMC, respectively, p=0.007). We investigated the phenotype of viral epitope-specific CD8(+) T cells identified with HLA-B53- and HLA-B58-peptide tetramers (8 HIV-2(+), 11 HIV-1(+) subjects). HIV-2-specific CD8(+) T cells were predominantly CD27(+) CD45RA(-), and only a minority expressed perforin. The limited breadth and low frequency of CD8(+) T cell responses to HIV-2 gag in aviremic HIV-2(+) subjects suggests that these responses reflect antigen load in plasma, as is the case in HIV-1 infection. Immune control of HIV-2 does not appear to be related to the frequency of perforin-expressing virus-specific CD8(+) T cells. 相似文献
20.
Yein‐Gei Lai Mau‐Sheng Hou Albert Lo Shih‐Ting Huang Yen‐Wen Huang Hsin‐Fang Yang‐Yen Nan‐Shih Liao 《European journal of immunology》2013,43(9):2305-2316
IL‐15 is an essential survival factor for CD8αα+ intestinal intraepithelial lymphocytes (iIELs) in vitro and in vivo. However, the IL‐15‐induced survival signals in primary CD8αα+ iIELs remains elusive. Although Bcl‐2 level in CD8αα+ iIELs positively correlates with IL‐15Rα expression in the intestinal epithelial cells, overexpression of Bcl‐2 only moderately restores CD8αα+ γδ iIELs in Il15?/? mice. Here, we found that IL‐15 promptly activated a Jak3‐Jak1‐PI3K‐Akt pathway that led to the upregulation of Bcl‐2 and Mcl‐1. This pathway also induced a delayed but sustained ERK1/2 activation, which not only was necessary for the maintenance of Bcl‐2 but also resulted in the phosphorylation of extra‐long Bim at Ser65. The latter event facilitated the dissociation of Bim from Bcl‐2 without affecting Bim abundance in IL‐15‐treated CD8αα+ iIELs. Using an adoptive cell transfer approach, we found that either overexpression of Bcl‐2 or removal of Bim from CD8αα+ iIELs promoted their survival in Il15ra?/? mice. Taken together, IL‐15 promotes CD8αα+ iIEL survival by both increasing Bcl‐2 levels and dissociating Bim from Bcl‐2 through activation of a Jak3‐Jak1‐PI3K‐Akt‐ERK1/2 pathway, which differs from a previously reported IL‐15‐induced survival signal. 相似文献