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3-Amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1) attenuates LPS-induced IL-8 expression by decreasing mRNA stability in THP-1 cells.
- Source :
-
Toxicology letters [Toxicol Lett] 2008 Mar 15; Vol. 177 (2), pp. 108-15. Date of Electronic Publication: 2008 Jan 06. - Publication Year :
- 2008
-
Abstract
- Heterocyclic amines (HCAs), such as Trp-P-1, PhIP, and IQ, are notorious food-born carcinogens. This study examined the inhibitory effects of HCAs on the expression of interleukin-8 (IL-8), which is an important chemokine for the initiation of innate immune responses that function by recruiting immune cells to inflamed sites. Among HCA types tested, only Trp-P-1 showed a robust inhibition of the lipopolysaccharide (LPS)-induced IL-8 expression at both mRNA and protein levels in a human monocytic cell-line, THP-1. However, Trp-P-1 did not inhibit the DNA-binding abilities of the transcription factors NF-kappaB, AP-1, and NF-IL6, all of which are known to regulate IL-8 transcription. Meanwhile, treatment with actinomycin D facilitated the Trp-P-1-induced down-regulation of IL-8 expression in LPS-stimulated THP-1 cells, implying that the inhibition might be due to a decrease in the stability of IL-8 mRNA rather than an attenuation of IL-8 transcription. Furthermore, Trp-P-1 also inhibited phosphorylation of p38 MAP kinase, which is involved in the regulation of IL-8 mRNA stability. Exogenous addition of ionomycin rescued both the IL-8 protein levels and phosphorylation of p38 MAP kinase inhibited by Trp-P-1. Collectively, these results suggest that Trp-P-1 suppresses LPS-induced IL-8 production in human monocytic cells through down-regulation of an intracellular calcium/p38 MAP kinase-dependent pathway, leading to the reduction of IL-8 mRNA stability.
- Subjects :
- CCAAT-Enhancer-Binding Protein-beta metabolism
Calcium metabolism
Cell Line
DNA Adducts toxicity
Down-Regulation
Humans
Imidazoles toxicity
Interleukin-8 genetics
Ionomycin metabolism
Lipopolysaccharides immunology
Monocytes drug effects
Monocytes immunology
NF-kappa B metabolism
Phosphorylation drug effects
Quinolines toxicity
RNA, Messenger metabolism
Transcription Factor AP-1 metabolism
p38 Mitogen-Activated Protein Kinases drug effects
p38 Mitogen-Activated Protein Kinases metabolism
Carbolines toxicity
Carcinogens toxicity
Immunity drug effects
Interleukin-8 antagonists & inhibitors
RNA Stability drug effects
RNA, Messenger drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 0378-4274
- Volume :
- 177
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Toxicology letters
- Publication Type :
- Academic Journal
- Accession number :
- 18281166
- Full Text :
- https://doi.org/10.1016/j.toxlet.2008.01.002