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Title: Stimulation of toll-like receptor 2 with bleomycin results in cellular activation and secretion of pro-inflammatory cytokines and chemokines

Abstract

The clinical use of bleomycin results in systemic and pulmonary inflammatory syndromes that are mediated by the production of cytokines and chemokines. In this study, we demonstrate that cell activation is initiated upon the recognition of bleomycin as a pathogen-associated molecular pattern by toll-like receptor (TLR) 2. The THP1 human monocytic cell line, which constitutively expresses high levels of TLR2, secretes interleukin (IL)-1{beta}, IL-8, and tumor necrosis factor (TNF)-{alpha} during bleomycin exposure. The TLR2-dependent nature of cell activation and cytokine secretion is supported by (1) the inability of TLR2-deficient human embryonic kidney (HEK) 293 cells to exhibit nuclear factor-kappa B (NF-{kappa}B) activation and secrete IL-8 in response to bleomycin; (2) the acquired ability of HEK293 to exhibit NF-{kappa}B activation and secrete IL-8 upon experimental expression of TLR2; and (3) the inhibition of cell activation in TLR2-expressing HEK293 and THP1 by anti-TLR2 monoclonal antibody. Collectively, these observations identify TLR2 activation as a critical event that triggers NF-{kappa}B activation and secretion of cytokines and chemokines during bleomycin exposure. Our in vitro findings could serve as a molecular mechanism underlying the pro-inflammatory toxicity associated with bleomycin. Whether bleomycin engages with other cellular receptors that results in activation of alternate signaling pathways and whethermore » the TLR2-agonist activity of bleomycin contribute to its anti-neoplastic property deserve further study.« less

Authors:
 [1];  [2];  [3];  [4]
  1. Division of Infectious Diseases and Internal Medicine, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905 (United States) and Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285 (United States). E-mail: Razonable.raymund@mayo.edu
  2. Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285 (United States)
  3. Division of Infectious Diseases and Internal Medicine, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905 (United States)
  4. (United States)
Publication Date:
OSTI Identifier:
20783417
Resource Type:
Journal Article
Resource Relation:
Journal Name: Toxicology and Applied Pharmacology; Journal Volume: 210; Journal Issue: 3; Other Information: DOI: 10.1016/j.taap.2005.05.002; PII: S0041-008X(05)00213-9; Copyright (c) 2005 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; BLEOMYCIN; IN VITRO; INFLAMMATION; INHIBITION; KIDNEYS; LYMPHOKINES; MONOCLONAL ANTIBODIES; PATHOGENS; RECEPTORS; SECRETION; STIMULATION; TOXICITY

Citation Formats

Razonable, Raymund R., Henault, Martin, Paya, Carlos V., and Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285. Stimulation of toll-like receptor 2 with bleomycin results in cellular activation and secretion of pro-inflammatory cytokines and chemokines. United States: N. p., 2006. Web. doi:10.1016/j.taap.2005.05.002.
Razonable, Raymund R., Henault, Martin, Paya, Carlos V., & Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285. Stimulation of toll-like receptor 2 with bleomycin results in cellular activation and secretion of pro-inflammatory cytokines and chemokines. United States. doi:10.1016/j.taap.2005.05.002.
Razonable, Raymund R., Henault, Martin, Paya, Carlos V., and Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285. Wed . "Stimulation of toll-like receptor 2 with bleomycin results in cellular activation and secretion of pro-inflammatory cytokines and chemokines". United States. doi:10.1016/j.taap.2005.05.002.
@article{osti_20783417,
title = {Stimulation of toll-like receptor 2 with bleomycin results in cellular activation and secretion of pro-inflammatory cytokines and chemokines},
author = {Razonable, Raymund R. and Henault, Martin and Paya, Carlos V. and Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285},
abstractNote = {The clinical use of bleomycin results in systemic and pulmonary inflammatory syndromes that are mediated by the production of cytokines and chemokines. In this study, we demonstrate that cell activation is initiated upon the recognition of bleomycin as a pathogen-associated molecular pattern by toll-like receptor (TLR) 2. The THP1 human monocytic cell line, which constitutively expresses high levels of TLR2, secretes interleukin (IL)-1{beta}, IL-8, and tumor necrosis factor (TNF)-{alpha} during bleomycin exposure. The TLR2-dependent nature of cell activation and cytokine secretion is supported by (1) the inability of TLR2-deficient human embryonic kidney (HEK) 293 cells to exhibit nuclear factor-kappa B (NF-{kappa}B) activation and secrete IL-8 in response to bleomycin; (2) the acquired ability of HEK293 to exhibit NF-{kappa}B activation and secrete IL-8 upon experimental expression of TLR2; and (3) the inhibition of cell activation in TLR2-expressing HEK293 and THP1 by anti-TLR2 monoclonal antibody. Collectively, these observations identify TLR2 activation as a critical event that triggers NF-{kappa}B activation and secretion of cytokines and chemokines during bleomycin exposure. Our in vitro findings could serve as a molecular mechanism underlying the pro-inflammatory toxicity associated with bleomycin. Whether bleomycin engages with other cellular receptors that results in activation of alternate signaling pathways and whether the TLR2-agonist activity of bleomycin contribute to its anti-neoplastic property deserve further study.},
doi = {10.1016/j.taap.2005.05.002},
journal = {Toxicology and Applied Pharmacology},
number = 3,
volume = 210,
place = {United States},
year = {Wed Feb 01 00:00:00 EST 2006},
month = {Wed Feb 01 00:00:00 EST 2006}
}