S. pneumoniae induziert JNK- und AP-1-abhängige Zytokinfreisetzung durch Lungenepithelzellen

Schmeck, Bernd; Zahlten, Janine; Dje, P. N'Guessan; Moog, Kerstin; Laak, Vincent van; Opitz, Bastian; Mitchell, Thomas C.; Rosseau, Simone; Suttorp, N; Hippenstiel, Stefan

doi:10.1055/s-2006-933869

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“…75,76 It is this activation that might have been responsible for the normal LL-37-induced MCP-1 levels in the presence of the p38 inhibitor. The differential response of IL-8 is less readily explained, with previous reports on the use of JNK inhibitors sometimes reporting a dampening of IL-8 levels 77 and sometimes not. 78 Transcriptional control of IL-8 is complex and requires the interplay of several signalling pathways, including activation of AP-1 by JNK and stabilization of IL-8 mRNA by the p38 pathway.…”

Section: Discussionmentioning

confidence: 76%

Systems biology evaluation of immune responses induced by human host defence peptide LL-37 in mononuclear cells

et al. 2009

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The immune system is very complex, it involves the integrated regulation and expression of hundreds of proteins. To understand in greater detail how the human host defence immunomodulatory peptide LL-37 interacts with innate immunity, a systems approach was pursued. Polychromatic flow cytometry was employed to demonstrate that within human peripheral blood mononuclear cells, CD14+ monocytes, myeloid and plasmocytoid dendritic cells and T- and B-lymphocytes, all responded to LL-37, with the differential production of intracellular cytokines. Microarray analyses with CD14+ monocytes indicated the differential expression of 475 genes in response to stimulation with LL-37. To understand this complex response, bioinformatic interrogation, using InnateDB, of the gene ontology, signalling pathways and transcription factor binding sites was undertaken. Activation of the IkappaBalpha/NFkappaB, mitogen-activated protein kinases p38, ERK1/2 and JNK, and PI3K signalling pathways in response to LL-37 was demonstrated by pathway and ontology over-representation analyses, and confirmed experimentally by inhibitor studies. Computational analysis of the predicted transcription factor binding sites upstream of the genes that were regulated by LL-37 predicted the involvement of several transcription factors including NFkappaB and five novel factors, AP-1, AP-2, SP-1, E2F1, and EGR, which were experimentally confirmed to respond to LL-37 by performing transcription factor array studies on nuclear extracts from LL-37 treated mononuclear cells. These data are discussed as reflecting the integration of several responsive signalling pathways through the involvement of transcription factor complexes in gene expression activated by LL-37 in human mononuclear cells.

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