Interleukin-10 fails to modulate low shear stress-induced neointimal hyperplasia

John E. Rectenwald, Rebecca M. Minter, Lyle L. Moldawer, Zaher Abouhamze, Drake La Face, Elizabeth Hutchins, Thomas S. Huber, James M. Seeger, C. Keith Ozaki

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

Introduction. Overexpression of the anti-inflammatory cytokine interleukin-10 (IL-10) blocks atherosclerotic events in vivo, and IL-10 has been recently hailed as an "immunologic scalpel" for atherosclerosis. Alternatively, mice lacking IL-10 receiving atherogenic diets have increased occlusive lesions. It remains unclear whether such IL-10 modulation broadly applies to other forms of occlusive arterial remodeling. We hypothesized that lack of IL-10 would exacerbate, and exogenous or overexpression of IL-10 would abrogate low shear stress-induced neointimal hyperplasia (NIH). Methods. Wild-type (WT) and IL-10-deficient (IL-10-/-) mice underwent unilateral common carotid artery (CCA) ligation. Low shear stress in the patent ligated artery results in remodeling and formation of neointima containing BrdU and SMC α-actin-positive cells. Additional groups of WT mice underwent CCA ligation and were treated daily with intraperitoneal saline or 1 μg of human IL-10. Chronic delivery gene therapy approaches were also utilized to define the role of IL-10 signaling. WT mice were treated adventitially with 1 × 1010 adenovirus/green fluorescent protein (Ad/gfp) and an Ad/empty control to confirm the veracity of adventitial delivery. Then, Ad viral IL-10 (vIL-10), Ad/empty, and virus buffer alone were applied directly to the adventitia of the CAA immediately following ligation. In separate experiments, 1 × 1010 Ad/empty or Ad/vIL-10 was injected intramuscularly. CCAs were perfusion fixed 28 days postligation, the time at which NIH is near maximum. Results. IL-10-/- mice developed identical NIH areas compared to WT controls. Mice receiving IL-10 demonstrated NIH equivalent to saline controls. Mice receiving intramuscular or adventitial Ad/IL-10 developed high serum levels of IL-10 yet formed NIH areas similar to those of controls. Serum IL-10 levels were significantly higher (P = 0.04) with adventitial delivery. Mice treated adventitially with Ad/gfp showed reliable transfection of cells within the adventitia of CAA. No antibody to human IL-10 was found in the sera of intraperitoneal IL-10-treated mice, which failed to attenuate NIH. Conclusion. Under the conditions of this experiment, lack of IL-10 does not exacerbate low shear stress-induced NIH, nor does exogenous administration or overexpression of IL-10 attenuate it. Despite high serum levels of vIL-10 in mice treated with ad/vIL-10 adventitially, there appears to be no therapeutic effect despite the confirmed transfection of adventitial cells. Discrepancies between these findings and previous research may be related to IL-10 dosing, inflammation induced by the adenoviral vector, or disparities between the NIH models.

Original languageEnglish (US)
Pages (from-to)110-118
Number of pages9
JournalJournal of Surgical Research
Volume102
Issue number2
DOIs
StatePublished - Jan 1 2002

Fingerprint

Interleukin-10
Hyperplasia
Adventitia
Ligation
Common Carotid Artery
Green Fluorescent Proteins
Serum
Adenoviridae
Transfection
Atherogenic Diet
Neointima

Keywords

  • Adenovirus gene therapy, arterial remodeling
  • Atherosclerosis
  • Interleukin 10
  • Neointimal hyperplasia

ASJC Scopus subject areas

  • Surgery

Cite this

Interleukin-10 fails to modulate low shear stress-induced neointimal hyperplasia. / Rectenwald, John E.; Minter, Rebecca M.; Moldawer, Lyle L.; Abouhamze, Zaher; La Face, Drake; Hutchins, Elizabeth; Huber, Thomas S.; Seeger, James M.; Ozaki, C. Keith.

In: Journal of Surgical Research, Vol. 102, No. 2, 01.01.2002, p. 110-118.

Research output: Contribution to journalArticle

Rectenwald, JE, Minter, RM, Moldawer, LL, Abouhamze, Z, La Face, D, Hutchins, E, Huber, TS, Seeger, JM & Ozaki, CK 2002, 'Interleukin-10 fails to modulate low shear stress-induced neointimal hyperplasia', Journal of Surgical Research, vol. 102, no. 2, pp. 110-118. https://doi.org/10.1006/jsre.2001.6283
Rectenwald, John E. ; Minter, Rebecca M. ; Moldawer, Lyle L. ; Abouhamze, Zaher ; La Face, Drake ; Hutchins, Elizabeth ; Huber, Thomas S. ; Seeger, James M. ; Ozaki, C. Keith. / Interleukin-10 fails to modulate low shear stress-induced neointimal hyperplasia. In: Journal of Surgical Research. 2002 ; Vol. 102, No. 2. pp. 110-118.
@article{8fdef29036b6485e8d999891fa203369,
title = "Interleukin-10 fails to modulate low shear stress-induced neointimal hyperplasia",
abstract = "Introduction. Overexpression of the anti-inflammatory cytokine interleukin-10 (IL-10) blocks atherosclerotic events in vivo, and IL-10 has been recently hailed as an {"}immunologic scalpel{"} for atherosclerosis. Alternatively, mice lacking IL-10 receiving atherogenic diets have increased occlusive lesions. It remains unclear whether such IL-10 modulation broadly applies to other forms of occlusive arterial remodeling. We hypothesized that lack of IL-10 would exacerbate, and exogenous or overexpression of IL-10 would abrogate low shear stress-induced neointimal hyperplasia (NIH). Methods. Wild-type (WT) and IL-10-deficient (IL-10-/-) mice underwent unilateral common carotid artery (CCA) ligation. Low shear stress in the patent ligated artery results in remodeling and formation of neointima containing BrdU and SMC α-actin-positive cells. Additional groups of WT mice underwent CCA ligation and were treated daily with intraperitoneal saline or 1 μg of human IL-10. Chronic delivery gene therapy approaches were also utilized to define the role of IL-10 signaling. WT mice were treated adventitially with 1 × 1010 adenovirus/green fluorescent protein (Ad/gfp) and an Ad/empty control to confirm the veracity of adventitial delivery. Then, Ad viral IL-10 (vIL-10), Ad/empty, and virus buffer alone were applied directly to the adventitia of the CAA immediately following ligation. In separate experiments, 1 × 1010 Ad/empty or Ad/vIL-10 was injected intramuscularly. CCAs were perfusion fixed 28 days postligation, the time at which NIH is near maximum. Results. IL-10-/- mice developed identical NIH areas compared to WT controls. Mice receiving IL-10 demonstrated NIH equivalent to saline controls. Mice receiving intramuscular or adventitial Ad/IL-10 developed high serum levels of IL-10 yet formed NIH areas similar to those of controls. Serum IL-10 levels were significantly higher (P = 0.04) with adventitial delivery. Mice treated adventitially with Ad/gfp showed reliable transfection of cells within the adventitia of CAA. No antibody to human IL-10 was found in the sera of intraperitoneal IL-10-treated mice, which failed to attenuate NIH. Conclusion. Under the conditions of this experiment, lack of IL-10 does not exacerbate low shear stress-induced NIH, nor does exogenous administration or overexpression of IL-10 attenuate it. Despite high serum levels of vIL-10 in mice treated with ad/vIL-10 adventitially, there appears to be no therapeutic effect despite the confirmed transfection of adventitial cells. Discrepancies between these findings and previous research may be related to IL-10 dosing, inflammation induced by the adenoviral vector, or disparities between the NIH models.",
keywords = "Adenovirus gene therapy, arterial remodeling, Atherosclerosis, Interleukin 10, Neointimal hyperplasia",
author = "Rectenwald, {John E.} and Minter, {Rebecca M.} and Moldawer, {Lyle L.} and Zaher Abouhamze and {La Face}, Drake and Elizabeth Hutchins and Huber, {Thomas S.} and Seeger, {James M.} and Ozaki, {C. Keith}",
year = "2002",
month = "1",
day = "1",
doi = "10.1006/jsre.2001.6283",
language = "English (US)",
volume = "102",
pages = "110--118",
journal = "Journal of Surgical Research",
issn = "0022-4804",
publisher = "Academic Press Inc.",
number = "2",

}

TY - JOUR

T1 - Interleukin-10 fails to modulate low shear stress-induced neointimal hyperplasia

AU - Rectenwald, John E.

AU - Minter, Rebecca M.

AU - Moldawer, Lyle L.

AU - Abouhamze, Zaher

AU - La Face, Drake

AU - Hutchins, Elizabeth

AU - Huber, Thomas S.

AU - Seeger, James M.

AU - Ozaki, C. Keith

PY - 2002/1/1

Y1 - 2002/1/1

N2 - Introduction. Overexpression of the anti-inflammatory cytokine interleukin-10 (IL-10) blocks atherosclerotic events in vivo, and IL-10 has been recently hailed as an "immunologic scalpel" for atherosclerosis. Alternatively, mice lacking IL-10 receiving atherogenic diets have increased occlusive lesions. It remains unclear whether such IL-10 modulation broadly applies to other forms of occlusive arterial remodeling. We hypothesized that lack of IL-10 would exacerbate, and exogenous or overexpression of IL-10 would abrogate low shear stress-induced neointimal hyperplasia (NIH). Methods. Wild-type (WT) and IL-10-deficient (IL-10-/-) mice underwent unilateral common carotid artery (CCA) ligation. Low shear stress in the patent ligated artery results in remodeling and formation of neointima containing BrdU and SMC α-actin-positive cells. Additional groups of WT mice underwent CCA ligation and were treated daily with intraperitoneal saline or 1 μg of human IL-10. Chronic delivery gene therapy approaches were also utilized to define the role of IL-10 signaling. WT mice were treated adventitially with 1 × 1010 adenovirus/green fluorescent protein (Ad/gfp) and an Ad/empty control to confirm the veracity of adventitial delivery. Then, Ad viral IL-10 (vIL-10), Ad/empty, and virus buffer alone were applied directly to the adventitia of the CAA immediately following ligation. In separate experiments, 1 × 1010 Ad/empty or Ad/vIL-10 was injected intramuscularly. CCAs were perfusion fixed 28 days postligation, the time at which NIH is near maximum. Results. IL-10-/- mice developed identical NIH areas compared to WT controls. Mice receiving IL-10 demonstrated NIH equivalent to saline controls. Mice receiving intramuscular or adventitial Ad/IL-10 developed high serum levels of IL-10 yet formed NIH areas similar to those of controls. Serum IL-10 levels were significantly higher (P = 0.04) with adventitial delivery. Mice treated adventitially with Ad/gfp showed reliable transfection of cells within the adventitia of CAA. No antibody to human IL-10 was found in the sera of intraperitoneal IL-10-treated mice, which failed to attenuate NIH. Conclusion. Under the conditions of this experiment, lack of IL-10 does not exacerbate low shear stress-induced NIH, nor does exogenous administration or overexpression of IL-10 attenuate it. Despite high serum levels of vIL-10 in mice treated with ad/vIL-10 adventitially, there appears to be no therapeutic effect despite the confirmed transfection of adventitial cells. Discrepancies between these findings and previous research may be related to IL-10 dosing, inflammation induced by the adenoviral vector, or disparities between the NIH models.

AB - Introduction. Overexpression of the anti-inflammatory cytokine interleukin-10 (IL-10) blocks atherosclerotic events in vivo, and IL-10 has been recently hailed as an "immunologic scalpel" for atherosclerosis. Alternatively, mice lacking IL-10 receiving atherogenic diets have increased occlusive lesions. It remains unclear whether such IL-10 modulation broadly applies to other forms of occlusive arterial remodeling. We hypothesized that lack of IL-10 would exacerbate, and exogenous or overexpression of IL-10 would abrogate low shear stress-induced neointimal hyperplasia (NIH). Methods. Wild-type (WT) and IL-10-deficient (IL-10-/-) mice underwent unilateral common carotid artery (CCA) ligation. Low shear stress in the patent ligated artery results in remodeling and formation of neointima containing BrdU and SMC α-actin-positive cells. Additional groups of WT mice underwent CCA ligation and were treated daily with intraperitoneal saline or 1 μg of human IL-10. Chronic delivery gene therapy approaches were also utilized to define the role of IL-10 signaling. WT mice were treated adventitially with 1 × 1010 adenovirus/green fluorescent protein (Ad/gfp) and an Ad/empty control to confirm the veracity of adventitial delivery. Then, Ad viral IL-10 (vIL-10), Ad/empty, and virus buffer alone were applied directly to the adventitia of the CAA immediately following ligation. In separate experiments, 1 × 1010 Ad/empty or Ad/vIL-10 was injected intramuscularly. CCAs were perfusion fixed 28 days postligation, the time at which NIH is near maximum. Results. IL-10-/- mice developed identical NIH areas compared to WT controls. Mice receiving IL-10 demonstrated NIH equivalent to saline controls. Mice receiving intramuscular or adventitial Ad/IL-10 developed high serum levels of IL-10 yet formed NIH areas similar to those of controls. Serum IL-10 levels were significantly higher (P = 0.04) with adventitial delivery. Mice treated adventitially with Ad/gfp showed reliable transfection of cells within the adventitia of CAA. No antibody to human IL-10 was found in the sera of intraperitoneal IL-10-treated mice, which failed to attenuate NIH. Conclusion. Under the conditions of this experiment, lack of IL-10 does not exacerbate low shear stress-induced NIH, nor does exogenous administration or overexpression of IL-10 attenuate it. Despite high serum levels of vIL-10 in mice treated with ad/vIL-10 adventitially, there appears to be no therapeutic effect despite the confirmed transfection of adventitial cells. Discrepancies between these findings and previous research may be related to IL-10 dosing, inflammation induced by the adenoviral vector, or disparities between the NIH models.

KW - Adenovirus gene therapy, arterial remodeling

KW - Atherosclerosis

KW - Interleukin 10

KW - Neointimal hyperplasia

UR - http://www.scopus.com/inward/record.url?scp=0036352688&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0036352688&partnerID=8YFLogxK

U2 - 10.1006/jsre.2001.6283

DO - 10.1006/jsre.2001.6283

M3 - Article

VL - 102

SP - 110

EP - 118

JO - Journal of Surgical Research

JF - Journal of Surgical Research

SN - 0022-4804

IS - 2

ER -