title: Lactoferricin mediates anti-inflammatory and anti-catabolic effects via inhibition of IL-1 and LPS activity in the intervertebral disc.
abstract: The catabolic cytokine interleukin-1 (IL-1) and endotoxin lipopolysaccharide (LPS) are well-known inflammatory mediators involved in degenerative disc disease, and inhibitors of IL-1 and LPS may potentially be used to slow or prevent disc degeneration in vivo. Here, we elucidate the striking anti-catabolic and anti-inflammatory effects of bovine lactoferricin (LfcinB) in the intervertebral disc (IVD) via antagonism of both IL-1 and LPS-mediated catabolic activity using in vitro and ex vivo analyses. Specifically, we demonstrate the biological counteraction of LfcinB against IL-1 and LPS-mediated proteoglycan (PG) depletion, matrix-degrading enzyme production, and enzyme activity in long-term (alginate beads) and short-term (monolayer) culture models using bovine and human nucleus pulposus (NP) cells. LfcinB significantly attenuates the IL-1 and LPS-mediated suppression of PG production and synthesis, and thus restores PG accumulation and pericellular matrix formation. Simultaneously, LfcinB antagonizes catabolic factor mediated induction of multiple cartilage-degrading enzymes, including MMP-1, MMP-3, MMP-13, ADAMTS-4, and ADAMTS-5, in bovine NP cells at both mRNA and protein levels. LfcinB also suppresses the catabolic factor-induced stimulation of oxidative and inflammatory factors such as iNOS, IL-6, and toll-like receptor-2 (TLR-2) and TLR-4. Finally, the ability of LfcinB to antagonize IL-1 and LPS-mediated suppression of PG is upheld in an en bloc intradiscal microinjection model followed by ex vivo organ culture using both mouse and rabbit IVD tissue, suggesting a potential therapeutic benefit of LfcinB on degenerative disc disease in the future.
authors: Section of Rheumatology, Department of Biochemistry, Rush University Medical Center, Chicago, Illinois 60612, USA.
authors: Jae-Sung
authors: JS
authors: Kim
authors: Michael B
authors: MB
authors: Ellman
authors: Dongyao
authors: D
authors: Yan
authors: Howard S
authors: HS
authors: An
authors: Ranjan
authors: R
authors: Kc
authors: Xin
authors: X
authors: Li
authors: Di
authors: D
authors: Chen
authors: Guozhi
authors: G
authors: Xiao
authors: Gabriella
authors: G
authors: Cs-Szabo
authors: David W
authors: DW
authors: Hoskin
authors: Doug D
authors: DD
authors: Buechter
authors: Andre J
authors: AJ
authors: Van Wijnen
authors: Hee-Jeong
authors: HJ
authors: Im
mesh_terms: D000818:Animals; D002417:Cattle; D002470:Cell Survival / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007375:Interleukin-1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007403:Intervertebral Disc / Q000166:cytology / Q000378:metabolism* / Q000503:physiopathology; D007781:Lactoferrin / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000633:toxicity*; D017116:Low Back Pain / Q000188:drug therapy* / Q000503:physiopathology; D051379:Mice; D009924:Organ Culture Techniques; D011509:Proteoglycans / Q000096:biosynthesis / Q000187:drug effects; D011817:Rabbits
chemical_list: D007375:Interleukin-1; D008070:Lipopolysaccharides; D011509:Proteoglycans; C082171:lactoferricin B; D007781:Lactoferrin