Molecular mechanisms and effector functions of the human cathelicidin host defence peptide LL-37: modulation of cytokine IL-32γ-induced responses and inflammatory arthritis
| dc.contributor.author | Choi, Ka-Yee Grace | |
| dc.contributor.examiningcommittee | Wilkins, John (Internal Medicine) Uzonna, Jude (Immunology) Kung, Sam (Immunology) Diamond, Gill (University of Florida) | en_US |
| dc.contributor.supervisor | Mookherjee, Neeloffer (Immunology) | en_US |
| dc.date.accessioned | 2017-04-03T15:19:30Z | |
| dc.date.available | 2017-04-03T15:19:30Z | |
| dc.date.issued | 2016 | |
| dc.degree.discipline | Immunology | en_US |
| dc.degree.level | Doctor of Philosophy (Ph.D.) | en_US |
| dc.description.abstract | Current therapies for chronic inflammatory diseases often abrogate the immune functions required to fight infections. Human cathelicidin host defence peptide (HDP) LL-37 selectively suppresses pathogen-induced inflammation, without compromising resistance to infections. These unique dual abilities of LL-37 make it a promising candidate as an alternative therapeutic for treating chronic inflammatory diseases. The objective of this study was to investigate the effects of LL-37 and its derivative peptide IG-19 in cytokine-mediated inflammation. I demonstrated that LL-37 and IG-19 selectively suppressed cytokine IL-32γ-induced pro-inflammatory cytokines, without compromising the production of anti-inflammatory cytokines, and chemokines in human PBMC and macrophages. However, significant quantitative differences between LL-37 and IG-19-mediated chemokine productions suggested that the mechanisms underlying the activity of these two peptides were different. I showed that both peptides suppressed IL-32γ-mediated phosphorylation of the Src-kinase FYN(Y420), known to enhance inflammation. Contrastingly, phosphorylation of the dual phosphatase MKP-1(S359), a negative regulator of inflammation, was enhanced in response to both peptides. Similarly, both peptides increased the activity of p44/42MAPK, which phosphorylates and stabilizes MKP-1. These results suggested that MKP-1 may be a critical mediator of the immunomodulatory activity of these peptides. Bioinformatic interrogation revealed that direct interacting protein partners of MKP-1 were overrepresented in MAPK and NF-κB signalling pathways. Both peptides enhanced the phosphorylation of p38MAPK. However, contrasting to LL-37, IG-19 did not mediate the phosphorylation of JNK MAPK and IKK-α signaling intermediates involved in inflammation. This was consistent with observations that chemokine production was significantly lower in response to IG-19 compared to LL-37. These results suggested that IG-19 may be a better immunomodulatory therapeutic candidate compared to LL-37. As cytokine-mediated inflammation plays critical roles in the disease pathogenesis of inflammatory arthritis, I examined the effects of exogenous administration of IG-19 in a murine model of collagen-induced arthritis. Administration of IG-19 decreased disease severity, suppressed pro-inflammatory cytokines and anti-collagen antibodies, and mitigated cartilage destruction in the CIA mice. These results provide a rationale to further develop IG-19 as a therapeutic agent for chronic inflammatory arthritis. The advantage of HDP based therapy is the potential to control inflammation without compromising the patient’s ability to resolve infections. | en_US |
| dc.description.note | May 2017 | en_US |
| dc.identifier.uri | http://hdl.handle.net/1993/32183 | |
| dc.language.iso | eng | en_US |
| dc.rights | open access | en_US |
| dc.subject | Host defence peptide | en_US |
| dc.subject | Cathelicidin | en_US |
| dc.subject | Cytokine IL-32 | en_US |
| dc.subject | Inflammatory arthritis | en_US |
| dc.subject | Inflammation | en_US |
| dc.title | Molecular mechanisms and effector functions of the human cathelicidin host defence peptide LL-37: modulation of cytokine IL-32γ-induced responses and inflammatory arthritis | en_US |
| dc.type | doctoral thesis | en_US |