Increased expression of endoplasmic reticulum stress and unfolded protein response genes in peripheral blood mononuclear cells from patients with limited cutaneous systemic sclerosis and pulmonary arterial hypertension

Stefania Lenna, Alessandra G. Farina, Viktor Martyanov, Romy B. Christmann, Tammara A. Wood, Harrison W. Farber, Raffaella Scorza, Michael L. Whitfield, Robert Lafyatis, Maria Trojanowska

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

Objective Pulmonary arterial hypertension (PAH), a common complication of limited cutaneous systemic sclerosis (lcSSc), is associated with alterations of markers of inflammation and vascular damage in peripheral blood mononuclear cells (PBMCs). Endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) have been implicated in autoimmune and inflammatory diseases. The goal of this study was to assess whether markers of ER stress and the UPR are present in PBMCs from lcSSc patients with PAH. Methods PBMCs were purified from 36 healthy controls, 32 lcSSc patients with PAH, and 34 lcSSc patients without PAH. Gene expression in healthy control PBMCs stimulated with thapsigargin was analyzed by DNA microarray. Genes were validated by quantitative real-time reverse transcription-polymerase chain reaction in PBMCs from healthy controls and lcSSc patients. Results Several ER stress/UPR genes, including BiP, activating transcription factor 4 (ATF-4), ATF-6, and a spliced form of X-box binding protein 1, were up-regulated in PBMCs from lcSSc patients, with the highest levels in patients with PAH. Thapsigargin up-regulated heat-shock proteins (HSPs) and interferon (IFN)-regulated genes in PBMCs from healthy controls. Selected HSP genes (particularly DnaJB1) and IFN-related genes were also found at significantly elevated levels in PBMCs from lcSSc patients, while IFN regulatory factor 4 expression was significantly decreased. There was a positive correlation between DnaJB1 and severity of PAH (measured by pulmonary artery pressure) (r = 0.56, P <0.05) and between ER stress markers and interleukin-6 levels (r = 0.53, P <0.0001) in PBMCs from lcSSc patients. Conclusion This study demonstrates an association between select ER stress/UPR markers and lcSSc with PAH, suggesting that ER stress and the UPR may contribute to the altered function of circulating immune cells in lcSSc.

Original languageEnglish
Pages (from-to)1357-1366
Number of pages10
JournalArthritis and Rheumatism
Volume65
Issue number5
DOIs
Publication statusPublished - May 2013

Fingerprint

Unfolded Protein Response
Endoplasmic Reticulum Stress
Systemic Scleroderma
Heat-Shock Proteins
Pulmonary Hypertension
Blood Cells
Skin
Genes
Thapsigargin
Interferons
Activating Transcription Factor 4
Oligonucleotide Array Sequence Analysis
Pulmonary Artery
Autoimmune Diseases
Reverse Transcription
Blood Vessels
Interleukin-6
Inflammation

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy
  • Rheumatology
  • Pharmacology (medical)

Cite this

Increased expression of endoplasmic reticulum stress and unfolded protein response genes in peripheral blood mononuclear cells from patients with limited cutaneous systemic sclerosis and pulmonary arterial hypertension. / Lenna, Stefania; Farina, Alessandra G.; Martyanov, Viktor; Christmann, Romy B.; Wood, Tammara A.; Farber, Harrison W.; Scorza, Raffaella; Whitfield, Michael L.; Lafyatis, Robert; Trojanowska, Maria.

In: Arthritis and Rheumatism, Vol. 65, No. 5, 05.2013, p. 1357-1366.

Research output: Contribution to journalArticle

Lenna, Stefania ; Farina, Alessandra G. ; Martyanov, Viktor ; Christmann, Romy B. ; Wood, Tammara A. ; Farber, Harrison W. ; Scorza, Raffaella ; Whitfield, Michael L. ; Lafyatis, Robert ; Trojanowska, Maria. / Increased expression of endoplasmic reticulum stress and unfolded protein response genes in peripheral blood mononuclear cells from patients with limited cutaneous systemic sclerosis and pulmonary arterial hypertension. In: Arthritis and Rheumatism. 2013 ; Vol. 65, No. 5. pp. 1357-1366.
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abstract = "Objective Pulmonary arterial hypertension (PAH), a common complication of limited cutaneous systemic sclerosis (lcSSc), is associated with alterations of markers of inflammation and vascular damage in peripheral blood mononuclear cells (PBMCs). Endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) have been implicated in autoimmune and inflammatory diseases. The goal of this study was to assess whether markers of ER stress and the UPR are present in PBMCs from lcSSc patients with PAH. Methods PBMCs were purified from 36 healthy controls, 32 lcSSc patients with PAH, and 34 lcSSc patients without PAH. Gene expression in healthy control PBMCs stimulated with thapsigargin was analyzed by DNA microarray. Genes were validated by quantitative real-time reverse transcription-polymerase chain reaction in PBMCs from healthy controls and lcSSc patients. Results Several ER stress/UPR genes, including BiP, activating transcription factor 4 (ATF-4), ATF-6, and a spliced form of X-box binding protein 1, were up-regulated in PBMCs from lcSSc patients, with the highest levels in patients with PAH. Thapsigargin up-regulated heat-shock proteins (HSPs) and interferon (IFN)-regulated genes in PBMCs from healthy controls. Selected HSP genes (particularly DnaJB1) and IFN-related genes were also found at significantly elevated levels in PBMCs from lcSSc patients, while IFN regulatory factor 4 expression was significantly decreased. There was a positive correlation between DnaJB1 and severity of PAH (measured by pulmonary artery pressure) (r = 0.56, P <0.05) and between ER stress markers and interleukin-6 levels (r = 0.53, P <0.0001) in PBMCs from lcSSc patients. Conclusion This study demonstrates an association between select ER stress/UPR markers and lcSSc with PAH, suggesting that ER stress and the UPR may contribute to the altered function of circulating immune cells in lcSSc.",
author = "Stefania Lenna and Farina, {Alessandra G.} and Viktor Martyanov and Christmann, {Romy B.} and Wood, {Tammara A.} and Farber, {Harrison W.} and Raffaella Scorza and Whitfield, {Michael L.} and Robert Lafyatis and Maria Trojanowska",
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T1 - Increased expression of endoplasmic reticulum stress and unfolded protein response genes in peripheral blood mononuclear cells from patients with limited cutaneous systemic sclerosis and pulmonary arterial hypertension

AU - Lenna, Stefania

AU - Farina, Alessandra G.

AU - Martyanov, Viktor

AU - Christmann, Romy B.

AU - Wood, Tammara A.

AU - Farber, Harrison W.

AU - Scorza, Raffaella

AU - Whitfield, Michael L.

AU - Lafyatis, Robert

AU - Trojanowska, Maria

PY - 2013/5

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N2 - Objective Pulmonary arterial hypertension (PAH), a common complication of limited cutaneous systemic sclerosis (lcSSc), is associated with alterations of markers of inflammation and vascular damage in peripheral blood mononuclear cells (PBMCs). Endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) have been implicated in autoimmune and inflammatory diseases. The goal of this study was to assess whether markers of ER stress and the UPR are present in PBMCs from lcSSc patients with PAH. Methods PBMCs were purified from 36 healthy controls, 32 lcSSc patients with PAH, and 34 lcSSc patients without PAH. Gene expression in healthy control PBMCs stimulated with thapsigargin was analyzed by DNA microarray. Genes were validated by quantitative real-time reverse transcription-polymerase chain reaction in PBMCs from healthy controls and lcSSc patients. Results Several ER stress/UPR genes, including BiP, activating transcription factor 4 (ATF-4), ATF-6, and a spliced form of X-box binding protein 1, were up-regulated in PBMCs from lcSSc patients, with the highest levels in patients with PAH. Thapsigargin up-regulated heat-shock proteins (HSPs) and interferon (IFN)-regulated genes in PBMCs from healthy controls. Selected HSP genes (particularly DnaJB1) and IFN-related genes were also found at significantly elevated levels in PBMCs from lcSSc patients, while IFN regulatory factor 4 expression was significantly decreased. There was a positive correlation between DnaJB1 and severity of PAH (measured by pulmonary artery pressure) (r = 0.56, P <0.05) and between ER stress markers and interleukin-6 levels (r = 0.53, P <0.0001) in PBMCs from lcSSc patients. Conclusion This study demonstrates an association between select ER stress/UPR markers and lcSSc with PAH, suggesting that ER stress and the UPR may contribute to the altered function of circulating immune cells in lcSSc.

AB - Objective Pulmonary arterial hypertension (PAH), a common complication of limited cutaneous systemic sclerosis (lcSSc), is associated with alterations of markers of inflammation and vascular damage in peripheral blood mononuclear cells (PBMCs). Endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) have been implicated in autoimmune and inflammatory diseases. The goal of this study was to assess whether markers of ER stress and the UPR are present in PBMCs from lcSSc patients with PAH. Methods PBMCs were purified from 36 healthy controls, 32 lcSSc patients with PAH, and 34 lcSSc patients without PAH. Gene expression in healthy control PBMCs stimulated with thapsigargin was analyzed by DNA microarray. Genes were validated by quantitative real-time reverse transcription-polymerase chain reaction in PBMCs from healthy controls and lcSSc patients. Results Several ER stress/UPR genes, including BiP, activating transcription factor 4 (ATF-4), ATF-6, and a spliced form of X-box binding protein 1, were up-regulated in PBMCs from lcSSc patients, with the highest levels in patients with PAH. Thapsigargin up-regulated heat-shock proteins (HSPs) and interferon (IFN)-regulated genes in PBMCs from healthy controls. Selected HSP genes (particularly DnaJB1) and IFN-related genes were also found at significantly elevated levels in PBMCs from lcSSc patients, while IFN regulatory factor 4 expression was significantly decreased. There was a positive correlation between DnaJB1 and severity of PAH (measured by pulmonary artery pressure) (r = 0.56, P <0.05) and between ER stress markers and interleukin-6 levels (r = 0.53, P <0.0001) in PBMCs from lcSSc patients. Conclusion This study demonstrates an association between select ER stress/UPR markers and lcSSc with PAH, suggesting that ER stress and the UPR may contribute to the altered function of circulating immune cells in lcSSc.

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