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Global computational regulatory analysis of the anti-endotoxin effect of LL-37 Doho, Gregory Hyojun


LL-37, a human cationic peptide, selectively modulates the innate immune response by interacting with the effector cells of innate immunity. It has been demonstrated to stimulate chemokine production and protect against infection, as well as suppress the endotoxin/lipopolysaccharide (LPS)-mediated production of pro-inflammatory cytokines and endotoxic shock in mouse model experiments. Microarray experiments under these conditions have indicated that the expression of numerous genes is altered in the presence of LL-37 and/or LPS, but the mechanisms underlying these transcriptional changes and the immunomodulatory effects of LL-37 are poorly understood. Therefore a computational approach was applied to time course microarray data comprising gene sets upregulated in monocytic cells upon treatment with LPS, LL-37 or LPS and LL-37. Sets of co-expressed genes observed in microarray experiments were clustered by a variety of methods into related temporal gene expression patterns. Subsequently, the promoter regions of the genes in these clusters were analyzed to predict potential transcription factor binding sites (TFBS) and the application of rigorous statistics revealed over-represented TFBS. This then permitted the generation of hypotheses concerning the transcription factors and signaling pathways involved in the anti-endotoxin effect(s) of LL-37. These analyses indicated that LL-37 selectively neutralized the LPS-induced expression of genes with promoters containing the signatures of both nuclear factor (NF)-κB and transcription factors downstream of mitogen-activated protein kinase (MAPK) pathways. Other genes that remained upregulated in the presence of both LPS and LL-37 tended to be deficient in TFBS for NF-κB but did contain the MAPK-related and other TFBS. LL-37 alone tended to induce expression of genes with promoters that bound transcription factors downstream of ERK1/2 and p38, MAPK that are known to be activated by LL-37, but did not induce the expression of most pro-inflammatory genes. Thus these data extend previous hypotheses that selective suppression of the NF-κB pathway is one of the anti-endotoxin mechanisms of LL-37, and indicate that residual gene expression is controlled in part by MAPK pathways.

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