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Bone Marrow Mononuclear Cells Up-Regulate Toll-Like Receptor Expression and Produce Inflammatory Mediators in Response to Cigarette Smoke Extract

By Junmin Zhou, Erika A. Eksioglu, Nicole R. Fortenbery, Xianghong Chen, Huaquan Wang, Pearlie K. Epling-Burnette, Julie Y. Djeu and Sheng Wei


Several reports link cigarette smoking with leukemia. However, the effects of cigarette smoke extract (CSE) on bone marrow hematopoiesis remain unknown. The objective of this study was to elucidate the direct effects of cigarette smoke on human bone marrow hematopoiesis and characterize the inflammatory process known to result from cigarette smoking. Bone marrow mononuclear cells (BMCs) from healthy individuals when exposed to CSE had significantly diminished CFU-E, BFU-E and CFU-GM. We found increased nuclear translocation of the NF-κB p65 subunit and, independently, enhanced activation of AKT and ERK1/2. Exposure of BMCs to CSE induced IL-8 and TGF-β1 production, which was dependent on NF-κB and ERK1/2, but not on AKT. CSE treatment had no effect on the release of TNF-α, IL-10, or VEGF. Finally, CSE also had a significant induction of TLR2, TLR3 and TLR4, out of which, the up-regulation of TLR2 and TLR3 was found to be dependent on ERK1/2 and NF-κB activation, but not AKT. These results indicate that CSE profoundly inhibits the growth of erythroid and granulocyte-macrophage progenitors in the bone marrow. Further, CSE modulates NF-κB- and ERK1/2-dependent responses, suggesting that cigarette smoking may impair bone marrow hematopoiesis in vivo as well as induce inflammation, two processes that proceed malignant transformation

Topics: Research Article
Publisher: Public Library of Science
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Provided by: PubMed Central

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  23. (2003). Mechanical stress activates the nuclear factorkappaB pathway in skeletal muscle fibers: a possible role in Duchenne muscular dystrophy.
  24. (2006). Mitogen-activated protein kinase phosphatase-1 is required for cisplatin resistance.
  25. (2006). New players in TLR-mediated innate immunity: PI3K and small Rho GTPases.
  26. (1998). NF-kappa B and Rel proteins: evolutionarily conserved mediators of immune responses.
  27. (1997). NF-kappa B as a frequent target for immunosuppressive and anti-inflammatory molecules.
  28. (2009). NF-kappa B p50 regulates C/EBP alpha expression and inflammatory cytokine-induced neutrophil production.
  29. (1996). NF-kappa B: ten years after.
  30. (1999). NF-kappaB activation by tumour necrosis factor requires the Akt serine-threonine kinase.
  31. (1999). NF-kappaB is a target of AKT in antiapoptotic PDGF signalling.
  32. (2008). NF-kappaB mediates the survival of human bronchial epithelial cells exposed to cigarette smoke extract. Respir Res 9: 66. CSE Up-Regulates Inflammatory Mediators in BMCs PLoS
  33. (2008). Osteoblast-derived TGF-beta1 stimulates IL-8 release through AP-1 and NF-kappaB in human cancer cells.
  34. (2003). Osteopontin induces nuclear factor kappa Bmediated promatrix metalloproteinase-2 activation through I kappa B alpha / IKK signaling pathways, and curcumin (diferulolylmethane) down-regulates these pathways.
  35. (2003). Phosphatidylinositol 3-kinase is involved in Toll-like receptor 4-mediated cytokine expression in mouse macrophages.
  36. (2003). PI3K and negative regulation of TLR signaling.
  37. Sibiril Y Stem cells in myelotoxicity.
  38. (2003). TGFbeta signaling-deficient hematopoietic stem cells have normal self-renewal and regenerative ability in vivo despite increased proliferative capacity in vitro.
  39. (2011). The impact of smoking on outcomes among patients undergoing hematopoietic SCT for the treatment of acute leukemia.
  40. (2000). The response of human bone marrow to chronic cigarette smoking.
  41. (2001). Toll receptors in innate immunity.
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  43. (2000). Toll-like receptor 2-mediated NF-kappa B activation requires a Rac1-dependent pathway.
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