title: Anti-inflammatory effects of Bifidobacterium longum subsp infantis secretions on fetal human enterocytes are mediated by TLR-4 receptors.
abstract: The therapeutic and preventive application of probiotics for necrotizing enterocolitis (NEC) has been supported by more and more experimental and clinical evidence in which Toll-like receptor 4 (TLR-4) exerts a significant role. In immune cells, probiotics not only regulate the expression of TLR-4 but also use the TLR-4 to modulate the immune response. Probiotics may also use the TLR-4 in immature enterocytes for anti-inflammation. Here we demonstrate that probiotic conditioned media (PCM) from Bifidobacterium longum supp infantis but not isolated organisms attenuates interleukin-6 (IL-6) induction in response to IL-1β by using TLR-4 in a human fetal small intestinal epithelial cell line (H4 cells), human fetal small intestinal xenografts, mouse fetal small intestinal organ culture tissues, and primary NEC enterocytes. Furthermore, we show that PCM, using TLR-4, downregulates the mRNA expression of interleukin-1 receptor-associated kinase 2 (IRAK-2), a common adapter protein shared by IL-1β and TLR-4 signaling. PCM also reduces the phosphorylation of the activator-protein 1 (AP-1) transcription factors c-Jun and c-Fos in response to IL-1β stimulation in a TLR-4-dependent manner. This study suggests that PCM may use TLR-4 through IRAK-2 and via AP-1 to prevent IL-1β-induced IL-6 induction in immature enterocytes. Based on these observations, the combined use of probiotics and anti-TLR-4 therapy to prevent NEC may not be a good strategy.
authors: Mucosal Immunology and Biology Research Center, Massachusetts General Hospital for Children, Harvard Medical School, Boston, Massachusetts.
authors: Di
authors: D
authors: Meng
authors: Mucosal Immunology and Biology Research Center, Massachusetts General Hospital for Children, Harvard Medical School, Boston, Massachusetts.
authors: Weishu
authors: W
authors: Zhu
authors: Mucosal Immunology and Biology Research Center, Massachusetts General Hospital for Children, Harvard Medical School, Boston, Massachusetts.
authors: Kriston
authors: K
authors: Ganguli
authors: Mucosal Immunology and Biology Research Center, Massachusetts General Hospital for Children, Harvard Medical School, Boston, Massachusetts.
authors: Hai Ning
authors: HN
authors: Shi
authors: Mucosal Immunology and Biology Research Center, Massachusetts General Hospital for Children, Harvard Medical School, Boston, Massachusetts wwalker@partners.org.
authors: W Allan
authors: WA
authors: Walker
mesh_terms: D000818:Animals; D000070236:Bifidobacterium longum subspecies infantis; D002460:Cell Line; D017077:Culture Media, Conditioned / Q000494:pharmacology*; D020345:Enterocolitis, Necrotizing / Q000378:metabolism / Q000517:prevention & control*; D020895:Enterocytes / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D053583:Interleukin-1beta / Q000494:pharmacology; D015850:Interleukin-6 / Q000378:metabolism; D007421:Intestine, Small / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D015398:Signal Transduction / Q000187:drug effects; D051197:Toll-Like Receptor 4 / Q000378:metabolism*
chemical_list: D017077:Culture Media, Conditioned; D053583:Interleukin-1beta; D015850:Interleukin-6; D051197:Toll-Like Receptor 4
keywords: Bifidobacterium infants; Toll-like receptors; immature enterocytes; probiotic secretions