Dataset Information

Activation of the signal transducer and activator of transcription 1 signaling pathway in thymocytes from HIV-1-infected human thymus.

ABSTRACT: OBJECTIVE:To identify HIV-induced host factors in the severe combined immunodeficient (SCID)-hu Thy/Liv mouse that may contribute to HIV pathogenesis in the thymus. DESIGN:To identify genes specifically altered by HIV-1 infection using the cDNA microarray assay, SCID-hu Thy/Liv organs derived from the same donors were used. Therefore, no genetic variations existed between HIV and mock-infected samples. In addition, the 12-14 day post-infection timepoint was chosen because no significant thymocyte depletion was detected in HIV-infected Thy/Liv organs, so mRNA from the same cell types could be compared. METHODS:Using SCID-hu Thy/Liv mice constructed from the same donor tissues, we analysed the expression of 9183 host genes in response to HIV infection with cDNA microarrays. Expression of selected genes with more than threefold induction was confirmed by measuring RNA (reverse transcriptase-polymerase chain reaction; RT-PCR) and proteins. RESULTS:HIV-1 (JD or NL4-3) infection of the SCID-hu Thy/Liv mouse led to more than threefold induction of 19 genes, 12 of which were IFN-inducible and six were unknown EST clones. We confirmed induction by RT-PCR and protein blots. Both signal transducer and activator of transcription (STAT)1 and STAT2 proteins were induced, and STAT1 was also activated by phosphorylation at the Tyr701 and Ser727 sites in human thymus infected with HIV-JD or NL4-3. Treatment of human fetal thymus organ culture or human thymocytes with recombinant HIV-1 gp120 proteins also led to induction or activation of STAT1. CONCLUSION:HIV-1 infection of the thymus led to activation of the STAT1 signaling pathway in thymocytes, which may contribute to HIV-1 pathogenesis in the thymus.

SUBMITTER: Miller ED

PROVIDER: S-EPMC4415361 | biostudies-literature | 2003 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Activation of the signal transducer and activator of transcription 1 signaling pathway in thymocytes from HIV-1-infected human thymus.

Miller Eric D ED Smith Jonathan A JA Lichtinger Monika M Wang Liping L Su Lishan L

AIDS (London, England) 20030601 9

<h4>Objective</h4>To identify HIV-induced host factors in the severe combined immunodeficient (SCID)-hu Thy/Liv mouse that may contribute to HIV pathogenesis in the thymus.<h4>Design</h4>To identify genes specifically altered by HIV-1 infection using the cDNA microarray assay, SCID-hu Thy/Liv organs derived from the same donors were used. Therefore, no genetic variations existed between HIV and mock-infected samples. In addition, the 12-14 day post-infection timepoint was chosen because no signi ...[more]

PMID: 12799548

Similar Datasets

Project description:Study questionAre STAT3 signaling molecules differentially expressed in endometriosis?Summary answerLevels of phospho-STAT3 and HIF1A, its downstream signaling molecule, are significantly higher in eutopic endometrium from women with endometriosis when compared with women without the disease.What is known alreadyEndometriosis is an estrogen-dependent inflammatory condition. Interleukin 6 (IL-6) is an inflammatory survival cytokine known to induce prolonged activation of STAT3 via association with the IL-6 receptor.Study design, size, durationCross-sectional measurements of STAT3 and HIF1A protein levels in eutopic endometrium from women with endometriosis versus those without.Participants/materials, setting, methodsLevels of phospho-STAT3 (pSTAT3) and HIF1A were examined in the endometrium of patients with and without endometriosis as well as in a non-human primate animal model using western blot and immunohistochemical analysis.Main results and the role of chanceLevels of pSTAT3 were significantly higher in the eutopic endometrium from women with endometriosis when compared with women without the disease in both the proliferative and secretory phases. HIF1A is known to be stabilized by STAT3 and IL-6. Our immunohistochemistry results show abundant HIF1A expression within the eutopic endometrial epithelial cells of women with endometriosis. Furthermore, pSTAT3 and HIF1A proteins are co-localized in endometriosis. This aberrant activation of pSTAT3 and HIF1A is confirmed by sequential analysis of eutopic endometrium using a baboon animal model of induced endometriosis. Lastly, we confirmed this IL-6 induction of both STAT3 phosphorylation and HIF1A mRNA expression in Ishikawa human endometrial adenocarcinoma cell line.Limitations, reasons for cautionIshikawa cancer cell line was used to study a benign disease. The peritoneal fluid contains various inflammatory cytokines in addition to IL-6 and so it is possible that other cytokines may affect the activity and expression of STAT3 signaling molecules.Wider implications of the findingsOur results imply that aberrant activation of STAT3 signaling plays an important role in the pathogenesis of endometriosis. Our findings could progress in our understanding of the etiology and pathophysiology of endometriosis and potential therapeutic interventions by targeted pharmacological.Study funding/competing interestsThis work was supported by NIH R01 HD067721 (to S.L.Y and B.A.L) and NIH R01 HD057873 and American Cancer Society Research Grant RSG-12-084-01-TBG (to J.-W.J.). There are no conflicts of interest.

Project description:OBJECTIVE:Glomerular mesangial expansion and podocyte loss are important early features of diabetic nephropathy, whereas tubulointerstitial injury and fibrosis are critical for progression of diabetic nephropathy to kidney failure. Therefore, we analyzed the expression of genes in glomeruli and tubulointerstitium in kidney biopsies from diabetic nephropathy patients to identify pathways that may be activated in humans but not in murine models of diabetic nephropathy that fail to progress to glomerulosclerosis, tubulointerstitial fibrosis, and kidney failure. RESEARCH DESIGN AND METHODS:Kidney biopsies were obtained from 74 patients (control subjects, early and progressive type 2 diabetic nephropathy). Glomerular and tubulointerstitial mRNAs were microarrayed, followed by bioinformatics analyses. Gene expression changes were confirmed by real-time RT-PCR and immunohistological staining. Samples from db/db C57BLKS and streptozotocin-induced DBA/2J mice, commonly studied murine models of diabetic nephropathy, were analyzed. RESULTS:In human glomeruli and tubulointerstitial samples, the Janus kinase (Jak)-signal transducer and activator of transcription (Stat) pathway was highly and significantly regulated. Jak-1, -2, and -3 as well as Stat-1 and -3 were expressed at higher levels in patients with diabetic nephropathy than in control subjects. The estimated glomerular filtration rate significantly correlated with tubulointerstitial Jak-1, -2, and -3 and Stat-1 expression (R(2) = 0.30-0.44). Immunohistochemistry found strong Jak-2 staining in glomerular and tubulointerstitial compartments in diabetic nephropathy compared with control subjects. In contrast, there was little or no increase in expression of Jak/Stat genes in the db/db C57BLKS or diabetic DBA/2J mice. CONCLUSIONS:These data suggest a direct relationship between tubulointerstitial Jak/Stat expression and progression of kidney failure in patients with type 2 diabetic nephropathy and distinguish progressive human diabetic nephropathy from nonprogressive murine diabetic nephropathy.

Dataset Information

Activation of the signal transducer and activator of transcription 1 signaling pathway in thymocytes from HIV-1-infected human thymus.

Publications

Activation of the signal transducer and activator of transcription 1 signaling pathway in thymocytes from HIV-1-infected human thymus.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure