Nevins W. Todd

Baltimore VA Medical Center

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Sergei P. Atamas

Baltimore VA Medical Center

Irina G. Luzina

University of Maryland, Baltimore

Virginia Lockatell

University of Maryland, Baltimore

Feng Jiang

University of Maryland, Baltimore

Janaki Deepak

University of Maryland, Baltimore

Sanford A. Stass

University of Maryland, Baltimore

Allen Burke

University of Maryland, Baltimore

Pavel Kopach

University of Maryland, Baltimore

Ruth L. Katz

The University of Texas MD Anderson Cancer Center

Van K. Holden

University of Maryland, Baltimore

Cooperative Institutions

University of Maryland, Baltimore

149

Pulmonary and Critical Care Associates

Isabela State University

University of Maryland Medical Center

Baltimore VA Medical Center

University of Colorado Denver

University of Baltimore

Royal Brompton Hospital

The Ocean Cleanup

University of Maryland, College Park

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The IL-33/ST2 Axis Is Not Required for the Profibrotic Effect of IL-33 in the Lungs

American Journal of Respiratory Cell and Molecular Biology (2024)

Sergei P. Atamas Virginia Lockatell Nevins W. Todd Irina G. Luzina

Interleukin 1β

10.1165/rcmb.2023-0434le

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IFN-γ controls IL-33 protein level through a STAT1- and LMP2-dependent mechanism (CCR5P.268)

The Journal of Immunology (2014)

Pavel Kopach Virginia Lockatell Nevins W. Todd Irina G. Luzina Sergei P. Atamas

Abstract IL-33 levels and activity are differentially associated with Th1 and Th2 phenotypes. IL-33 mRNA is rapidly regulated but the fate of synthesized IL-33 protein is unknown. To assess the interplay between IL-33, IFN-γ, and IL-4 proteins, replication-deficient adenoviruses (AdV) were constructed for dual expression of IL-33 & IFN-γ or of IL-33 & IL-4. Combined IL-33 & IFN-γ or IL-33 & IL-4 effects were compared with similar AdV expression of each of these cytokines alone. Co-delivery of IL-33 & IFN-γ led to mutual suppression, and co-delivery of IL-33 & IL-4 led to mutual elevation of these proteins in cell culture and in vivo. Purified IFN-γ also attenuated IL-33 protein but not mRNA driven by the recombinant CMV promoter in AdV-IL-33-infected cells, suggesting that IFN-γ controls IL-33 protein degradation. Pharmacological inhibition, siRNA-mediated silencing, or gene deficiency of STAT1 potently upregulated IL-33 protein expression levels and attenuated the downregulating effect of IFN-γ on IL-33. Inhibition of caspase-1, -3, or -8 had minimal effect on IFN-γ-driven IL-33 protein downregulation. siRNA-mediated silencing of LMP2 proteasome subunit, which is known to be essential for IFN-γ-regulated antigen processing, also abrogated the effect of IFN-γ on IL-33. Thus, IL-33, IFN-γ, and IL-4 are engaged in a complex interplay, part of which involves IFN-γ-activated, caspase-independent, STAT1-mediated degradation of IL-33 protein through non-canonical use of LMP2 proteasome.

STAT1

Protein Degradation

10.4049/jimmunol.192.supp.181.22

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A Non-Coding RNA Landscape of Bronchial Epitheliums of Lung Cancer Patients

Biomedicines (2020)

Yanli Lin Van K. Holden Pushpawallie Dhilipkannah Janaki Deepak Nevins W. Todd

We propose to systematically identify a non-coding RNA (ncRNA) profile of exfoliated bronchial epitheliums of sputum from lung cancer patients. Bronchial epithelial cells enriched from sputum of 32 lung cancer patients and 33 cancer-free smokers were analyzed by next-generation sequencing to comprehensively characterize the ncRNA profiles. In addition, 108 miRNAs, 88 small nucleolar RNAs, 13 piwi-interacting RNAs, 6 transfer RNAs, 4 ribosomal RNAs, 19 small nuclear RNAs, and 25 long-noncoding (lnc) RNAs displayed a significantly different level in bronchial epitheliums of sputum of lung cancer patients versus cancer-free smokers (all <0.001). PCR analysis confirmed their different expression levels in the sputum specimens. A high expression of SNHG9, an lncRNA, was validated in 78 lung tumor tissues, and the expression was inversely associated with overall survival of lung cancer patients (

10.3390/biomedicines8040088

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Macrophages Produce TGF-β-Induced (β-ig-h3) following Ingestion of Apoptotic Cells and Regulate MMP14 Levels and Collagen Turnover in Fibroblasts

The Journal of Immunology (2008)

Natalia Nacu Irina G. Luzina Kendrick Highsmith Virginia Lockatell Kerill Pochetuhen

Abstract Phagocytic clearance of apoptotic cells by macrophages is an essential part in the resolution of inflammation. It coincides with activation of repair mechanisms, including accumulation of extracellular matrix. A possible link between clearance of apoptotic debris and accumulation of extracellular matrix has not been investigated. Production of collagen was measured in primary fibroblasts cocultured with macrophages. Ingestion of apoptotic cells by monocyte-derived macrophages led to up-regulation of collagen. Direct contact between macrophages and fibroblasts was not required for collagen up-regulation. Macrophages produced TGF-β following ingestion of apoptotic cells, but the levels of this cytokine were lower than those required for a significant up-regulation of collagen. Simultaneously, the levels of TGF-β-induced (TGFBI), or keratoepithelin/BIGH3, mRNA and protein were increased. In contrast, primary alveolar macrophages stimulated collagen production without exposure to apoptotic cells; there was no further increase in the levels of TGFBI, mRNA or protein, or collagen after ingestion of apoptotic cells. Stimulation of fibroblasts with TGFBI down-regulated MMP14 levels, decreased DNA binding by p53, increased DNA binding by PU.1, and up-regulated collagen protein but not mRNA levels. Overexpression of MMP14 or p53, or small interfering RNA-mediated inhibition of PU.1 led to an increase in MMP14 and a decline in collagen levels, whereas small interfering RNA-mediated inhibition of MMP14 led to elevation of collagen levels. In conclusion, monocyte-derived but not alveolar macrophages produce TGFBI following ingestion of apoptotic cells, leading to the down-regulation of MMP14 levels in fibroblasts through a mechanism involving p53 and PU.1, and to subsequent accumulation of collagen.

10.4049/jimmunol.180.7.5036

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Alternatively spliced variants of interleukin-4 promote inflammation differentially

Journal of Leukocyte Biology (2011)

Irina G. Luzina Virginia Lockatell Nevins W. Todd Kendrick Highsmith Achsah Keegan

ABSTRACT IL-4δ2 is a natural splice variant of IL-4 that lacks the region encoded by the second exon. Numerous reports have suggested that the expression levels of IL-4δ2 change in various diseases, especially those with pulmonary involvement, but the in vivo effects of this splice variant have never been studied. Replication-deficient, AdV-mediated gene delivery of mIL-4δ2 to mouse lungs in vivo was used, and the effects compared with similar adenoviral delivery of mIL-4 or with infection with a noncoding NULL viral construct. Overexpression of IL-4δ2 or IL-4 caused pulmonary infiltration by T and B lymphocytes, whereas in contrast to IL-4, IL-4δ2 did not induce eosinophilia or goblet cell hyperplasia. Microarray analysis of global gene expression revealed that IL-4δ2 and IL-4 had differential effects on gene expression. These splice variants also differentially regulated pulmonary levels of the cytokines TNF-α, eotaxin, IL-1α, IFN-γ, and MCP-1, whereas both tended to increase total lung collagen modestly. Pulmonary infiltration by lymphocytes in response to overexpression of IL-4δ2 was attenuated but not abrogated completely by germline deficiency of IL-4Rα or STAT6, whereas deficiency of endogenous IL-4 had no effect. Thus, IL-4δ2 promotes lymphocytic inflammation in vivo (although differentially from IL-4, in part), and the effects of IL-4δ2 are not mediated by endogenous IL-4. Differential targeting of IL-4δ2 and IL-4 may therefore be considered in developing future therapeutic agents.

10.1189/jlb.0510271

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A comprehensive assessment of environmental exposures and the medical history guides multidisciplinary discussion in interstitial lung disease

Respiratory Medicine (2021)

N. Dodia D. Amariei Blaine Kenaa Doug Corwin Lydia Chelala

Hypersensitivity pneumonitis

Medical History

Histopathology

10.1016/j.rmed.2021.106333

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Elevated expression of NEU1 sialidase in idiopathic pulmonary fibrosis provokes pulmonary collagen deposition, lymphocytosis, and fibrosis

AJP Lung Cellular and Molecular Physiology (2016)

Irina G. Luzina Virginia Lockatell Sang Won Hyun Pavel Kopach Phillip Kang

Idiopathic pulmonary fibrosis (IPF) poses challenges to understanding its underlying cellular and molecular mechanisms and the development of better therapies. Previous studies suggest a pathophysiological role for neuraminidase 1 (NEU1), an enzyme that removes terminal sialic acid from glycoproteins. We observed increased NEU1 expression in epithelial and endothelial cells, as well as fibroblasts, in the lungs of patients with IPF compared with healthy control lungs. Recombinant adenovirus-mediated gene delivery of NEU1 to cultured primary human cells elicited profound changes in cellular phenotypes. Small airway epithelial cell migration was impaired in wounding assays, whereas, in pulmonary microvascular endothelial cells, NEU1 overexpression strongly impacted global gene expression, increased T cell adhesion to endothelial monolayers, and disrupted endothelial capillary-like tube formation. NEU1 overexpression in fibroblasts provoked increased levels of collagen types I and III, substantial changes in global gene expression, and accelerated degradation of matrix metalloproteinase-14. Intratracheal instillation of NEU1 encoding, but not control adenovirus, induced lymphocyte accumulation in bronchoalveolar lavage samples and lung tissues and elevations of pulmonary transforming growth factor-β and collagen. The lymphocytes were predominantly T cells, with CD8 + cells exceeding CD4 + cells by nearly twofold. These combined data indicate that elevated NEU1 expression alters functional activities of distinct lung cell types in vitro and recapitulates lymphocytic infiltration and collagen accumulation in vivo, consistent with mechanisms implicated in lung fibrosis.

10.1152/ajplung.00346.2015

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Citations (41)

Plasma Micrornas Are Potential Biomarkers For Non-Small Cell Lung Cancer

He Zhang Feng Jiang Jun Shen Jeipi Liao Maria Guarnera

10.1164/ajrccm-conference.2011.183.1_meetingabstracts.a5154

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Endobronchial Actinomycosis Associated With Foreign Body: An Unusual Cause Of Pneumonia And Endobronchial Mass

Ayal Romem Sachin Patel Nevins W. Todd

Actinomycosis

10.1164/ajrccm-conference.2011.183.1_meetingabstracts.a5698