Abstract
Bovine lactoferricin (LfcinB), a multifunctional peptide, was recently demonstrated to be anti-catabolic and anti-inflammatory in human articular cartilage. LfcinB blocks IL-1-mediated proteoglycan depletion, matrix-degrading enzyme expression, and pro-inflammatory mediator induction. LfcinB selectively activates ERK1/2, p38 (but not JNK), and Akt signaling. However, the relationship between these pathways and LfcinB target genes has never been explored. In this study, we uncovered the remarkable ability of LfcinB in the induction of an anti-inflammatory cytokine, IL-11. LfcinB binds to cell surface heparan sulfate to initiate ERK1/2 signaling and activate AP-1 complexes composed of c-Fos and JunD, which transactivate the IL-11 gene. The induced IL-11 functions as an anti-inflammatory and chondroprotective cytokine in articular chondrocytes. Our data show that IL-11 directly attenuates IL-1-mediated catabolic and inflammatory processes ex vivo and in vitro. Moreover, IL-11 activates STAT3 signaling pathway to critically up-regulate TIMP-1 expression, as a consecutive secondary cellular response after IL-11 induction by LfcinB-ERK-AP-1 axis in human adult articular chondrocytes. The pathological relevance of IL-11 signaling to osteoarthritis is evidenced by significant down-regulation of its cognate receptor expression in osteoarthritic chondrocytes. Together, our results suggest a two-step mechanism, whereby LfcinB induces TIMP-1 through an IL-11-dependent pathway involving transcription factor AP-1 and STAT3.
Highlights
Bovine lactoferricin (LfcinB) promotes anti-catabolism and anti-inflammation in articular cartilage
LfcinB Induces IL-11 via the ERK1/2-c-Fos/JunD Axis—Previously, we reported robust activation of ERK1/2 and Akt by LfcinB, which sustains for Ͼ60 min in human articular chondrocytes [11]
STAT3 signaling is not required for LfcinB-mediated IL-11 expression, it is essential to IL-11-mediated tissue inhibitor of metalloproteinase 1 (TIMP-1) expression
Summary
Bovine lactoferricin (LfcinB) promotes anti-catabolism and anti-inflammation in articular cartilage. Conclusion: LfcinB sequentially regulates IL-11 and TIMP-1 expression through distinct mechanisms in articular chondrocytes. Bovine lactoferricin (LfcinB), a multifunctional peptide, was recently demonstrated to be anti-catabolic and anti-inflammatory in human articular cartilage. LfcinB selectively activates ERK1/2, p38 (but not JNK), and Akt signaling. LfcinB binds to cell surface heparan sulfate to initiate ERK1/2 signaling and activate AP-1 complexes composed of c-Fos and JunD, which transactivate the IL-11 gene. IL-11 activates STAT3 signaling pathway to critically up-regulate TIMP-1 expression, as a consecutive secondary cellular response after IL-11 induction by LfcinB-ERK-AP-1 axis in human adult articular chondrocytes. Our results suggest a two-step mechanism, whereby LfcinB induces TIMP-1 through an IL-11dependent pathway involving transcription factor AP-1 and STAT3
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