Transcriptional regulation of the human cathelicidin antimicrobial peptide gene Public Deposited

http://ir.library.oregonstate.edu/concern/graduate_thesis_or_dissertations/ng451n209

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  • Human cathelicidin antimicrobial peptide (CAMP/LL-37) is a cationic antimicrobial peptide that is widely expressed by myeloid and epithelial cells at the human-environment interface. It possesses broad spectrum antimicrobial capacity against bacteria, fungi and viruses. In addition to its direct antimicrobial activity, CAMP/LL-37 also attracts and recruits monocytes, neutrophils and other immune cells to fight infections. It plays an essential role in innate immunity. Mice lacking the cathelicidin gene are more susceptible to skin, urinary and pulmonary tract infections. Likewise, CAMP deficiency in humans is linked to higher incidences of both bacterial and viral infections. This dissertation presents three chapters of original research focusing on the transcriptional regulation of the human CAMP gene. All three chapters are manuscripts that are either published or ready to submit for publication. Studies described in Chapter 2 were designed to identify alternative vitamin D receptor (VDR) ligands that regulate the CAMP gene. Previous studies had suggested that curcumin and certain polyunsaturated fatty acids (PUFAs) were putative alternative VDR agonists. 1α,25-dihydroxyvitamin D₃ (1,25(OH)₂D₃) induces CAMP gene expression by activating the VDR and so we determined if these alternative ligand candidates also activated the CAMP gene in human myeloid and epithelial cells. We found that curcumin, but not PUFAs, induced the CAMP gene at both the mRNA and protein levels. Unexpectedly, curcumin induction of CAMP was independent of the VDR. Chapter 3 summarizes our efforts to identify additional pathways that regulate CAMP expression. In these experiments, a cell-based CAMP luciferase reporter system was used to screen a National Institute of Health (NIH) Clinical Collection of 446 molecules that are extensively studied in both basic research and clinical trials. Two stilbenoids, pterostilbene and resveratrol, activated the luciferase reporter and also up-regulated the endogenous CAMP gene in U937 and HaCaT cells in presence of 1,25(OH)₂D₃. Results from these two chapters indicate that naturally occurring dietary factors are potentially important regulators of innate immunity. In chapter 4, we examined the complex crosstalk between vitamin D and Toll-like receptor (TLR) signaling pathways. We showed that TLR3 and TLR4 agonists significantly suppress vitamin D-induced CAMP expression by inhibiting retinoid-Xreceptor α (RXRα) expression, which is required for VDR transactivation. These findings expand our understanding of the role of TLRs in CAMP regulation and provide a potential mechanism explaining virus-induced secondary bacterial infections.In addition, our results suggest that IKKε/Tank-binding kinase 1 (TBK1) was required for this suppression, thus identifying a potential therapeutic target in secondary bacterial infections.
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  • description.provenance : Submitted by Chunxiao Guo (guoc@onid.orst.edu) on 2013-08-09T22:32:29Z No. of bitstreams: 2 license_rdf: 1232 bytes, checksum: bb87e2fb4674c76d0d2e9ed07fbb9c86 (MD5) GuoChunxiao2013.pdf: 3501016 bytes, checksum: cca30c960cd778e9d541a01cba02fd61 (MD5)
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  • description.provenance : Approved for entry into archive by Julie Kurtz(julie.kurtz@oregonstate.edu) on 2013-08-13T16:43:05Z (GMT) No. of bitstreams: 2 license_rdf: 1232 bytes, checksum: bb87e2fb4674c76d0d2e9ed07fbb9c86 (MD5) GuoChunxiao2013.pdf: 3501016 bytes, checksum: cca30c960cd778e9d541a01cba02fd61 (MD5)
  • description.provenance : Approved for entry into archive by Laura Wilson(laura.wilson@oregonstate.edu) on 2013-08-15T15:45:40Z (GMT) No. of bitstreams: 2 license_rdf: 1232 bytes, checksum: bb87e2fb4674c76d0d2e9ed07fbb9c86 (MD5) GuoChunxiao2013.pdf: 3501016 bytes, checksum: cca30c960cd778e9d541a01cba02fd61 (MD5)

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