Pentoxifylline protects L929 fibroblasts from TNF-alpha toxicity via the induction of heme oxygenase-1.
Tumor necrosis factor-alpha (TNF-alpha) is recognized as a principal mediator of a variety of inflammatory conditions. Pentoxifylline (PTX), which can inhibit cellular TNF-alpha synthesis, also attenuates the toxic effect of TNF-alpha. However, the mechanism underlying PTX-induced cytoprotection is unknown. Heme oxygenase 1 (HO-1) is an enzyme which degrades heme into biliverdin, free iron, and carbon monoxide (CO). This enzyme has recently been shown to have anti-inflammatory and cytoprotective effects. In this study, we investigated whether protection by PTX against TNF-alpha-mediated toxicity could be related to its ability to induce HO-1 expression and HO activity in L929 cells. PTX in the range of 0.1-1.0mM significantly induced HO-1 expression and the resulting HO activity. Pre-incubation of L929 cells with either PTX or the HO activator hemin resulted in the protection of the cells against TNF-alpha-mediated toxicity. Zinc protoporphyrin, a specific HO competitive inhibitor, abrogated the protective effect of PTX. Hemoglobin, a scavenger of CO, reversed the protective effect of PTX. A cytoprotection comparable to PTX was observed when the cells were treated with the CO-releasing compound tricarbonyldichlororuthenium(II) dimer. These results suggest that HO-1 expression and the ensuing formation of the HO metabolite CO may be a novel pathway by which PTX protects L929 cells from TNF-alpha-mediated toxicity.
Oh
Gi-Su
GS
Medicinal Resources Research Center (MRRC), Wonkwang University, Iksan, Chonbuk 570-749, Republic of Korea.
Pae
Hyun-Ock
HO
Moon
Mi-Kyung
MK
Choi
Byung-Min
BM
Yun
Young-Gab
YG
Rim
Joung-Sik
JS
Chung
Hun-Taeg
HT
D015153:Blotting, Western; D002384:Catalysis; D002460:Cell Line; D004790:Enzyme Induction / Q000187:drug effects*; D005347:Fibroblasts / Q000187:drug effects*; D006419:Heme Oxygenase (Decyclizing) / Q000096:biosynthesis*; D051547:Heme Oxygenase-1; D010431:Pentoxifylline / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
D014409:Tumor Necrosis Factor-alpha; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; D010431:Pentoxifylline