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Neutrophil-derived lactoferrin induces the inflammatory responses of rheumatoid arthritis synovial fibroblasts via Toll-like receptor 4
K. Umekita1, S. Miyauchi2, H. Nomura3, K. Umeki4, A. Okayama5
- Department of Rheumatology, Infectious Diseases, and Laboratory Medicine, Faculty of Medicine, University of Miyazaki, Japan. kunihiko_umekita@med.miyazaki-u.ac.jp
- Department of Rheumatology, Infectious Diseases, and Laboratory Medicine, Faculty of Medicine, University of Miyazaki, Japan.
- Department of Rheumatology, Infectious Diseases, and Laboratory Medicine, Faculty of Medicine, University of Miyazaki, Japan.
- Department of Rheumatology, Infectious Diseases, and Laboratory Medicine, Faculty of Medicine, University of Miyazaki, Japan.
- Department of Rheumatology, Infectious Diseases, and Laboratory Medicine, Faculty of Medicine, University of Miyazaki, Japan.
CER11434
2019 Vol.37, N°5
PI 0834, PF 0841
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PMID: 30767875 [PubMed]
Received: 30/05/2018
Accepted : 17/12/2018
In Press: 11/02/2019
Published: 29/08/2019
Abstract
OBJECTIVES:
Damage-associated molecular patterns (DAMPs) are proposed to drive aberrant stimulation of Toll-like receptors (TLRs) in rheumatoid arthritis (RA) inflamed joints. In the current study we investigated the role of the neutrophil-derived lactoferrin (LTF), as an endogenous ligand for TLR4 in the inflammatory response of RA synovial fibroblasts (RASFs).
METHODS:
RASFs were stimulated with LTF, and the expressions of inflammatory cytokines in RASFs were measured. To clarify the TLR4 signalling pathway associated with LTF stimulation, a small molecular inhibitor of TLR4 (TAK242) and NF-κB inhibitor were used. The role of nuclear factor of activated T cells 5 (NFAT5) was identified using small interfering RNA. To reveal the interaction between NF-κB and NFAT5, cerulenin, which disrupts their interaction, was used.
RESULTS:
Stimulation of RASFs with LTF significantly increased the expressions of inflammatory cytokines and chemokines, such as IL-6, CCL20 and IL-8, in RASFs. LTF enhanced the mRNA expressions of these cytokines in RASFs stimulated by TNF-α. TAK242 almost completely inhibited the expressions of inflammatory cytokines and chemokines in RASFs stimulated by LTF. The NF-κB inhibitor partially repressed the expressions of IL-6 and IL-8 mRNAs induced by LTF, but not CCL20 mRNA expression. On the other hand, NFAT5 silencing decreased the expressions of CCL20 and IL-8 mRNAs induced by LTF, but not IL-6 mRNA expression. Cerulenin repressed the expressions of IL-6, CCL20 and IL-8 in RASFs stimulated by LTF.
CONCLUSIONS:
Neutrophil-derived LTF may play a role as an endogenous ligand for TLR4 expressed on RASFs. NFAT5-NF-κB enhanceosome might regulate the expressions of LTF-TLR4-responsive genes in RASFs.
