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Dive into the research topics where Sreerama Shetty is active.

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Featured researches published by Sreerama Shetty.


Journal of Immunology | 2006

Vimentin Expressed on Mycobacterium tuberculosis-Infected Human Monocytes Is Involved in Binding to the NKp46 Receptor

Ankita Garg; Peter F. Barnes; Angel Porgador; Sugata Roy; Shiping Wu; Jagpreet S. Nanda; David E. Griffith; William M. Girard; Nenoo Rawal; Sreerama Shetty; Ramakrishna Vankayalapati

We previously showed that human NK cells used the NKp46 receptor to lyse Mycobacterium tuberculosis H37Ra-infected monocytes. To identify ligands on H37Ra-infected human mononuclear phagocytes, we used anti-NKp46 to immunoprecipitate NKp46 from NK cells bound to its ligand(s) on H37Ra-infected monocytes. Mass spectrometry analysis identified a 57-kDa molecule, vimentin, as a putative ligand for NKp46. Vimentin expression was significantly up-regulated on the surface of infected monocytes, compared with uninfected cells, and this was confirmed by fluorescence microscopy. Anti-vimentin antiserum inhibited NK cell lysis of infected monocytes, whereas antiserum to actin, another filamentous protein, did not. CHO-K1 cells transfected with a vimentin construct were lysed much more efficiently by NK cells than cells transfected with a control plasmid. This lysis was inhibited by mAb-mediated masking of NKp46 (on NK cells) or vimentin (on infected monocytes). ELISA and Far Western blotting showed that recombinant vimentin bound to a NKp46 fusion protein. These results indicate that vimentin is involved in binding of NKp46 to M. tuberculosis H37Ra-infected mononuclear phagocytes.


Journal of Immunology | 2003

Urokinase-Type Plasminogen Activator Potentiates Lipopolysaccharide-Induced Neutrophil Activation

Edward Abraham; Margaret R. Gyetko; Katherine Kuhn; John J. Arcaroli; Derek Strassheim; Jong Sung Park; Sreerama Shetty; Steven Idell

Urokinase plasminogen activator (uPA) is a serine protease that catalyzes the conversion of plasminogen to plasmin. Although increased circulating levels of uPA are present in endotoxemia and sepsis, conditions in which activated neutrophils contribute to the development of acute organ dysfunction, the ability of uPA to participate directly in LPS-induced neutrophil activation has not been examined. In the present experiments, we show that uPA can enhance activation of neutrophils exposed to submaximal stimulatory doses of LPS. In particular, uPA increased LPS-induced activation of intracellular signaling pathways, including Akt and c-Jun N-terminal kinase, nuclear translocation of the transcriptional regulatory factor NF-κB, and expression of proinflammatory cytokines, including IL-1β, macrophage-inflammatory protein-2, and TNF-α. There was no effect of uPA on LPS-induced activation of p38 mitogen-activated protein kinase in neutrophils. Transgenic mice unable to produce uPA (uPA−/−) were protected from endotoxemia-induced lung injury, as determined by development of lung edema, pulmonary neutrophil accumulation, lung IL-1β, macrophage-inflammatory protein-2, and TNF-α cytokine levels. These results demonstrate that uPA can potentiate LPS-induced neutrophil responses and also suggest that such effects are sufficiently important in vivo to play a major contributory role in neutrophil-mediated inflammatory responses, such as the development of acute lung injury.


American Journal of Physiology-lung Cellular and Molecular Physiology | 2012

δ ENaC: a novel divergent amiloride-inhibitable sodium channel

Hong Long Ji; Run Zhen Zhao; Zai Xing Chen; Sreerama Shetty; Steven Idell; Sadis Matalon

The fourth subunit of the epithelial sodium channel, termed delta subunit (δ ENaC), was cloned in human and monkey. Increasing evidence shows that this unique subunit and its splice variants exhibit biophysical and pharmacological properties that are divergent from those of α ENaC channels. The widespread distribution of epithelial sodium channels in both epithelial and nonepithelial tissues implies a range of physiological functions. The altered expression of SCNN1D is associated with numerous pathological conditions. Genetic studies link SCNN1D deficiency with rare genetic diseases with developmental and functional disorders in the brain, heart, and respiratory systems. Here, we review the progress of research on δ ENaC in genomics, biophysics, proteomics, physiology, pharmacology, and clinical medicine.


American Journal of Physiology-lung Cellular and Molecular Physiology | 2008

The fibrinolytic system and the regulation of lung epithelial cell proteolysis, signaling, and cellular viability

Sreerama Shetty; Joseph Padijnayayveetil; Torry A. Tucker; Dorota Stankowska; Steven Idell

The urokinase-type plasminogen activator (uPA), its receptor (uPAR), and plasminogen activator inhibitor-1 (PAI-1) are key components of the fibrinolytic system and are expressed by lung epithelial cells. uPA, uPAR, and PAI-1 have been strongly implicated in the pathogenesis of acute lung injury (ALI) and pulmonary fibrosis. Recently, it has become clear that regulation of uPA, uPAR, and PAI-1 occurs at the posttranscriptional level of mRNA stability in lung epithelial cells. uPA further mediates its own expression in these cells as well as that of uPAR and PAI-1 through induction of changes in mRNA stability. In addition, uPA-mediated signaling controls the expression of the tumor suppressor protein p53 in lung epithelial cells at the posttranslational level. p53 has recently been shown to be a trans-acting uPA, uPAR, and PAI-1 mRNA-binding protein that regulates the stability of these mRNAs. It is now clear that signaling initiated by uPA mediates dose-dependent regulation of lung epithelial cell apoptosis and likewise involves changes in p53, uPA, uPAR, and PAI-1 expression. These findings demonstrate that the uPA-uPAR-PAI-1 system of lung epithelial cells mediates a broad repertoire of responses that encompass but extend well beyond traditional fibrinolysis, involve newly recognized interactions with p53 that influence the viability of the lung epithelium, and are thereby implicated in the pathogenesis of ALI and its repair.


Molecular and Cellular Biochemistry | 2005

Regulation of urokinase receptor mRNA stability by hnRNP C in lung epithelial cells.

Sreerama Shetty

Increased urokinase receptor (uPAR) expression as well as stabilisation of uPAR mRNA contribute to the pathogenesis of lung inflammation and neoplasia. Post-transcriptional regulation of uPAR mRNA involves interaction of both coding and 3′-UTR sequences with regulatory uPAR mRNA binding proteins (Bps). In order to identify novel regulatory interactions, we performed gel mobility shift and UV cross-linking assays and found two distinct uPAR mRNA-protein complexes. We identified a rapidly migrating 40 kDa uPAR mRNABp that selectively bound a 110 nucleotide (nt) fragment of the uPAR mRNA 3′UTR. Chimeric β-globin/uPAR mRNA containing the 110 nt 40 kDa protein binding fragment destabilised stable β-globin mRNA with a rate of decay identical to that of chimeric β-globin/uPAR containing the full uPAR 3′UTR. The 40 kDa uPAR 3′UTR Bp was purified using poly (U) sepharose and identified as heterogeneous nuclear ribonucleoprotein C (hnRNPC). Finally, we confirmed its interaction with the uPAR mRNA 3′ UTR by gel mobility supershift assay using an anti-hnRNPC antibody. Direct in vivo interaction of hnRNPC with the uPAR mRNA 3′UTR was demonstrated by immunoprecipitation and combined RT PCR-Southern blotting assay. Co-transfection of hnRNPC cDNA in Beas2B cells reversed destabilisation of chimeric β-globin/uPAR 3′UTR mRNA and its over-expression also induced uPAR protein and mRNA expression through stabilisation of uPAR mRNA. These observations indicate a novel mechanism of uPAR gene regulation in lung epithelial cells in which cis elements within a 110 nt uPAR mRNA 3′UTR sequence interact with hnRNPC to regulate uPAR mRNA stability.


Journal of Biological Chemistry | 2001

Urokinase Induces Expression of Its Own Receptor in Beas2B Lung Epithelial Cells

Sreerama Shetty; Steven Idell

Interaction between the urokinase-type plasminogen activator (uPA) and its receptor (uPAR) localizes cellular proteolysis and promotes cellular proliferation and migration. The interaction between uPA and uPAR at the surface of epithelial cells thereby contributes to the pathogenesis of lung inflammation and neoplasia. In this study, we sought to determine if uPA itself alters uPAR expression by lung epithelial cells. uPA enhanced uPAR expression as well as 125I-uPA binding in Beas2B lung epithelial cells in a time- and concentration-dependent manner. The uPA-mediated induction of uPAR is not accomplished through its receptor and requires enzymatic activity. The low molecular weight fragment of uPA, lacking the receptor binding domain, was as potent as intact two-chain uPA in inducing expression of uPAR at the cell surface. Plasmin, the end product of plasminogen activation, did not alter uPA-mediated uPAR expression. Induction of uPAR by uPA represents a novel pathway by which epithelial cells can regulate uPAR-dependent cellular responses that may contribute to stromal remodeling in lung injury or neoplasia.


American Journal of Physiology-lung Cellular and Molecular Physiology | 2015

Sirt1 restrains lung inflammasome activation in a murine model of sepsis

Rong Gao; Zhongsen Ma; Yuxin Hu; Jiao Chen; Sreerama Shetty; Jian Fu

Excessive inflammation is a major cause of organ damage during sepsis. The elderly are highly susceptible to sepsis-induced organ injury. Sirt1 expression is reduced during aging. In the present study, we investigated the role of Sirt1, a histone deacetylase, in controlling inflammatory responses in a murine sepsis model induced by cecal ligation and puncture (CLP). We examined lung inflammatory signaling in inducible Sirt1 knockout (Sirt1(-/-)) mice and wild-type littermates (Sirt1(+/+)) after CLP. Our results demonstrated that Sirt1 deficiency led to severe lung inflammatory injury. To further investigate molecular mechanisms of Sirt1 regulation of lung inflammatory responses in sepsis, we conducted a series of experiments to assess lung inflammasome activation after CLP. We detected increased lung inflammatory signaling including NF-κB, signal transducer and activator of transcription 3, and ERK1/2 activation in Sirt1(-/-) mice after CLP. Furthermore, inflammasome activity was increased in Sirt1(-/-) mice after CLP, as demonstrated by increased IL-1β and caspase-7 cleavage and activation. Aggravated inflammasome activation in Sirt1(-/-) mice was associated with the increased production of lung proinflammatory mediators, including ICAM-1 and high-mobility group box 1, and further disruption of tight junctions and adherens junctions, as demonstrated by dramatic reduction of lung claudin-1 and vascular endothelial-cadherin expression, which was associated with the upregulation of matrix metallopeptidase 9 expression. In summary, our results suggest that Sirt1 suppresses acute lung inflammation during sepsis by controlling inflammasome activation pathway.


Journal of Biological Chemistry | 2008

Regulation of Plasminogen Activator Inhibitor-1 Expression by Tumor Suppressor Protein p53

Sreerama Shetty; Praveenkumar Shetty; Steven Idell; Thirunavukkarasu Velusamy; Yashodhar P. Bhandary; Rashmi S. Shetty

H1299 lung carcinoma cells lacking p53 (p53-/-) express minimal amounts of plasminogen activator inhibitor-1 (PAI-1) protein as well as mRNA. p53-/- cells express highly unstable PAI-1 mRNA. Transfection of p53 in p53-/- cells enhanced PAI-1 expression and stabilized PAI-1 mRNA. On the contrary, inhibition of p53 expression by RNA silencing in non-malignant human lung epithelial (Beas2B) cells decreased basal as well as urokinase-type plasminogen activator-induced PAI-1 expression because of accelerated degradation of PAI-1 mRNA. Purified p53 protein specifically binds to the PAI-1 mRNA 3′-un-translated region (UTR), and endogenous PAI-1 mRNA forms an immune complex with p53. Treatment of purified p53 protein with anti-p53 antibody abolished p53 binding to the 3′-UTR of PAI-1 mRNA. The p53 binding region maps to a 70-nucleotide PAI-1 mRNA 3′-UTR sequence, and insertion of the p53-binding sequence into β-globin mRNA destabilized the chimeric transcript. Deletion experiments indicate that the carboxyl-terminal region (amino acid residues 296–393) of p53 protein interacts with PAI-1 mRNA. These observations demonstrate a novel role for p53 as an mRNA-binding protein that regulates increased PAI-1 expression and stabilization of PAI-1 mRNA in human lung epithelial and carcinoma cells.


Inflammation Research | 2002

Pseudomonas aeruginosa elastase stimulates ERK signaling pathway and enhances IL- 8 production by alveolar epithelial cells in culture

Ali O. Azghani; J. W. Baker; Sreerama Shetty; E. J. Miller; G. J. Bhat

Abstract:Objective and design: Bacterial products as well as the host airway inflammatory responses contribute to the pathogenesis of Pseudomonas infections. We sought to determine if Pseudomonas elastase (PE) induces mitogen-activated protein (MAP) kinase activity in association with interleukin-8 (IL-8) production by alveolar epithelial cells.¶Methods: We utilized Western blot analysis to detect phosphorylation of signaling intermediates and ELISA was used to measure IL-8 production.¶Results: We found that PE induces phosphorylation of the extracellular signal-regulated (ERK1/2) proteins of the MAPK pathway in A549 epithelial cells. Similar results were obtained using primary cultures of rabbit alveolar type II epithelial cells. PE also enhanced IL-8 production, which was abolished in the presence of the ERK activation inhibitor U0126.¶Conclusions: We conclude that PE activates the ERK1/2 arm of the MAPK pathway and that activation of this pathway results in enhanced IL-8 production. The results demonstrate that PE may augment pulmonary inflammation via cellular signaling that regulates expression of IL-8.


Molecular and Cellular Biochemistry | 1999

Posttranscriptional regulation of urokinase receptor gene expression in human lung carcinoma and mesothelioma cells in vitro

Sreerama Shetty; Steven Idell

The urokinase-type plasminogen activator (uPA) interacts with its receptor (uPAR) to promote proteolysis as well as cell proliferation and migration. These functions contribute to the pathogenesis of neoplastic growth and invasiveness. Expression of uPAR in tumor extracts also inversely correlates with prognosis in many forms of cancer. In this study, we sought to determine if differences in uPAR expression were distinguishable between cultured human lung carcinoma and malignant mesothelioma subtypes. We also sought to determine if, as in malignant mesothelioma cells, uPAR expression is regulated at the posttranscriptional level in cultured malignant lung carcinoma cells. Using 125I-uPA binding and ligand blotting techniques, uPAR was expressed by phenotypically diverse lung carcinoma cell lines, including the H460, H157 and H1395 non-small cell lines and the H146 small cell lung carcinoma line. Increased uPAR expression was also detected in spindle-shaped (M33K) and epithelioid (M9K and MS-1) malignant mesothelioma cells. Selected mediators, including TGF-β, TNF-α, LPS and PMA, uniformly enhanced uPAR expression in each of the tumor cell lines. Steady state uPAR mRNA expression was determined by RNase protection assay and correlated directly with the changes in cell surface uPAR expression. By gel mobility shift and UV-cross linking assays, a uPAR mRNA binding protein (uPAR mRNABp) implicated in the posttranscriptional control of message stability, was identified in each of the cell lines. Expression of uPAR and its message in cultured lung carcinoma and malignant mesothelioma cells is similarly influenced by effectors present in the tumor microenvironment. Regulation of the uPAR message occurs at the posttranscriptional level in cultured small and non-small cell lung carcinoma cells as well as spindle-shaped and fibrous malignant mesothelioma cell lines. Posttranscriptional regulation of uPAR in all these cells involves the interaction of the uPAR mRNABp with uPAR mRNA, which promotes uPAR mRNA destabilization.

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Steven Idell

University of Texas Health Science Center at Tyler

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Yashodhar P. Bhandary

University of Texas Health Science Center at Tyler

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Jian Fu

University of Kentucky

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Amarnath S. Marudamuthu

University of Texas Health Science Center at Tyler

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Shwetha K. Shetty

University of Texas Health Science Center at Tyler

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Rashmi S. Shetty

University of Texas Health Science Center at Tyler

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Thirunavukkarasu Velusamy

University of Texas Health Science Center at Tyler

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Praveenkumar Shetty

University of Texas Health Science Center at Tyler

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Galina Florova

University of Texas Health Science Center at Tyler

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Hong Long Ji

University of Texas Health Science Center at Tyler

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