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. / May 2017