Abstract
Mounting evidence suggests that the host defence peptide, LL-37, plays a role in both inflammation and in wound healing; however, the role of this peptide in the remodeling and maintenance of oral tissues is not yet fully understood. Fibroblasts are the most abundant cell type within the periodontal tissues, and gingival fibroblasts play an important role in maintaining and repairing the gingival tissues which are constantly exposed to external insults. In this study we examined the direct effects of LL-37 treatment on gingival fibroblasts and found that LL-37 significantly increased secretion of both interleukin 8 (IL-8) and IL-6 from these cells. LL-37 tended to decrease matrix metalloproteinase (MMP) activity in gingival fibroblasts, but this decrease did not reach statistical significance. LL-37 significantly increased tissue inhibitor of metalloproteinase-1 (TIMP-1) production by gingival fibroblasts, but had no significant effect on TIMP-2 levels. LL-37 was also shown to significantly increase production of basic fibroblast growth factor (bFGF), hepatocyte growth factor (HGF), and keratinocyte growth factor (KGF) in gingival fibroblasts. Taken together, these results suggest an important role for the host defence peptide, LL-37, in modulating the fibroblast response to remodeling in periodontal tissues.
Highlights
Human cathelicidin is an 18 kDa protein [1], derived from the cathelicidin family of host defence peptides, and is the only cathelicidin protein in humans [2,3]
Based on the adage that LL-37, at concentrations ≥5 μg/mL, has a range of biological functions [8,19] and the fact that concentrations above this exhibited the greatest effect on pro-inflammatory cytokine and tissue inhibitor of metalloproteinase-1 (TIMP-1) production by gingival fibroblasts, we investigated the effects of LL-37 on growth factor expression at concentrations of 0.2 and 2 μM
hepatocyte growth factor (HGF) is produced by gingival fibroblasts in response to Porphyromonas gingivalis LPS and in response to other bacterial pathogen-associated molecular patterns (PAMPs) [31,32]; in this study we show that HGF is produced in response to LL-37
Summary
Human cathelicidin (hCAP18) is an 18 kDa protein [1], derived from the cathelicidin family of host defence peptides, and is the only cathelicidin protein in humans [2,3]. Mice deficient in the murine cathelicidin, CRAMP, exhibited increased risk of necrotising skin infections, supporting the theory. Neutrophils from patients with morbus Kostmann syndrome, a severe congenital neutropenia, are deficient in hCAP18/LL-37 and these patients suffer from recurrent bacterial infections. They suffer from severe periodontal disease, suggesting an important role for LL-37 in prevention of infection and resolution of inflammation in oral tissues [10,11]
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