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.
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.
Im
Jintaek
J
Department of Oral Microbiology & Immunology, Dental Research Institute, and BK21 Program, School of Dentistry, Seoul National University, Seoul 110-749, Republic of Korea.
Kang
Seok-Seong
SS
Yang
Jae Seung
JS
Yun
Cheol-Heui
CH
Yang
Young
Y
Han
Seung Hyun
SH
D022782:CCAAT-Enhancer-Binding Protein-beta / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002243:Carbolines / Q000633:toxicity*; D002273:Carcinogens / Q000633:toxicity*; D002460:Cell Line; D018736:DNA Adducts / Q000633:toxicity; D015536:Down-Regulation; D006801:Humans; D007093:Imidazoles / Q000633:toxicity; D007109:Immunity / Q000187:drug effects*; D016209:Interleukin-8 / Q000037:antagonists & inhibitors* / Q000235:genetics; D015759:Ionomycin / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology; D009000:Monocytes / Q000187:drug effects / Q000276:immunology; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011804:Quinolines / Q000633:toxicity; D020871:RNA Stability / Q000187:drug effects*; D012333:RNA, Messenger / Q000187:drug effects* / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism
D022782:CCAAT-Enhancer-Binding Protein-beta; D002243:Carbolines; D002273:Carcinogens; D018736:DNA Adducts; C096278:DNA-(2-amino-3-methylimidazo(4,5-f)quinoline) adduct; D007093:Imidazoles; D016209:Interleukin-8; D008070:Lipopolysaccharides; D016328:NF-kappa B; D011804:Quinolines; D012333:RNA, Messenger; D018808:Transcription Factor AP-1; D015759:Ionomycin; C049584:2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine; D048051:p38 Mitogen-Activated Protein Kinases; C019132:3-amino-1,4-dimethyl-5H-pyrido(4,3-b)indole; D002118:Calcium