Abstract
Intestinal cytochrome P450 subclass 1A1 (CYP1A1) contributes to a metabolic “shield” protecting the host from ingested carcinogens such as polycyclic aromatic hydrocarbons (PAH). The expression of CYP1 (including CYP1A2 and CYP1B1) is considered to depend solely on a heterodimeric transcription factor consisting of the arylhydrocarbon receptor (AHR) and the AHR nuclear translocator (ARNT). So far, no interference has been noted between the regulation of CYP1 and the activation of Toll-like receptor 2 (TLR2), which modulates the inflammatory response to bacterial cell wall components in immune cells and enterocytes. Here we report that intestinal CYP1A1 is silenced in TLR2-deficient mice, even when under exposure to the carcinogenic PAH benzo[a]pyrene (BaP). In contrast, hepatic CYP1A1 was moderately induced in TLR2-deficient mice without restoring their ability to clear BaP from systemic circulation, as present in wild-type animals. After feeding of BaP for 21 days, only TLR2−/− mice, but not their wild type littermates developed polyps in the colon. Gene expressions and protein concentrations of AHR and ARNT in the intestine did not differ between the genotypes. In conclusion, the presence of ligands for TLR2 of bacterial origin seems to be crucial for detoxication of luminal carcinogens by CYP1A1 in the intestine. This unprecedented finding indicates a complex interplay between the immune system of the host and intestinal bacteria with detoxication mechanisms. This highlights the relevance of intestinal microbiota when trying to unravel pathways present in mammals and opens new perspectives for research in human health.
Highlights
The toll-like receptor (TLR) family comprises a group of type 1 transmembrane glycoproteins, which recognize microbe-associated molecular patterns (MAMPs) [1]
Out of all measured gene expressions, that of the Cyp1a1 gene was changed the most – its expression was negligible in the intestines of mice that did not express functional Toll-like receptor 2 (TLR2) (22-fold reduction compared to WT animals)
In the consequent intervention study, we investigated whether feeding with BaP induces expression of intestinal mRNAs for cytochrome P450 subclass 1A1 (CYP1A1), CYP1A2, and CYP1B1 as well as concentrations of cytochrome P450 (CYP) 1A1/CYP1A2 protein in TLR22/2 mice and in wild-type animals
Summary
The toll-like receptor (TLR) family comprises a group of type 1 transmembrane glycoproteins, which recognize microbe-associated molecular patterns (MAMPs) [1]. Binding of MAMPs to these receptors induces innate immune responses such as cytokine production, phagocytosis initiation, antigen presentation and other molecular events resulting in inflammation and its autoregulation [2]. Toll-like receptor 2 (TLR2) in association with TLR1 or TLR6 is crucial for recognition of bacterial lipoproteins, lipopeptides, and other microbial cell wall components [3] and consequent induction of pro-inflammatory responses predominantly in polymorphonuclear leukocytes and phagocytes [4]. TLR2, together with TLR1 or TLR6, signals as part of a heterodimer in association with lymphocyte antigen 96 (MD2) by recruitment of myeloid differentiation primary response protein 88 (MyD88), toll-interleukin 1 receptor (TIR) domain containing adaptor protein (TIRAP), and toll-like receptor adaptor molecule 2 (TICAM2), to their intracellular signaling domains [5]. Some bacteria, which are considered to have probiotic properties and harbour ligands for TLR2, have been discussed as protective agents in colon cancer development [7]
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