Molecular mechanisms and effector functions of the human cathelicidin host defence peptide LL-37: modulation of cytokine IL-32γ-induced responses and inflammatory arthritis

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Choi, Ka-Yee Grace
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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.
Host defence peptide, Cathelicidin, Cytokine IL-32, Inflammatory arthritis, Inflammation