Fatty Acids Promote Secretion of Proinflammatory and Prodestructive Factors by Synovial Fibroblasts

Klaus W. Frommer¹, Andreas Schäffler², Stefan Rehart³, Angela Lehr⁴, Ulf Müller-Ladner⁵ and Elena Neumann⁶, ¹Internal Medicine and Rheumatology, Justus-Liebig-University of Gießen, Kerckhoff-Klinik, Bad Nauheim, Germany, ²Department of Internal Medicine III, Endocrinology, Diabetes, Metabolism, Justus-Liebig-University of Giessen, Giessen, Germany, ³Orthopedics and Trauma Surgery, Markus-Hospital, Frankfurt, Germany, ⁴Dept Orthopedics and Trauma Surgery, Markus-Hospital, Frankfurt, Germany, ⁵Department of Internal Medicine and Rheumatology, Justus-Liebig-University of Gießen, Bad Nauheim, Germany, ⁶Department of Internal Medicine and Rheumatology, Justus-Liebig-University of Gießen, Kerckhoff-Klinik, Bad Nauheim, Germany

Meeting: 2012 ACR/ARHP Annual Meeting

Keywords: Fibroblasts

Session Information

Title: Cytokines, Mediators, and Gene Regulation

Session Type: Abstract Submissions (ACR)

Background/Purpose: Due to their role in inflammatory metabolic diseases, we hypothesized that free fatty acids (FFA) are also involved in primary inflammatory joint diseases including rheumatoid arthritis (RA) and psoriasis arthritis (PsA) as well as in degenerative joint diseases with secondary inflammatory properties, specifically osteoarthritis (OA). To test this hypothesis, we analyzed the effect of FFA on synovial fibroblasts (SF), a key cell type in the pathophysiology of arthritis. We also investigated whether FFA need to be internalized to have an effect and if the innate immune system is involved in the modulation of this effect.

Methods: RASF, OASF and PsASF were stimulated in vitro with different saturated and unsaturated FFA within their physiological range of concentrations. Immunoassays were used to quantify FFA-induced protein secretion. Sulfosuccinimidyl oleate sodium (SSO) was used to inhibit the fatty acid translocase (FAT), which is responsible for transporting long-chain fatty acids into the cell. In addition, TLR4 signaling, which can contribute to driving arthritis, was inhibited intracellularly and extracellularly.

Results: In RASF, FFA dose-dependently enhanced the secretion of the proinflammatory cytokine IL-6, the chemokines IL-8 and MCP-1, as well as the matrix-degrading enzymes MMP-1 and MMP-3. Cell population, cell source (RA, OA, or PsA) and the respective molecular parameters were factors that influenced the changes of protein secretion (e.g. for lauric acid [100 µM] with RASF / IL-6: 9.1-fold increase; IL‑8: 14.9‑fold increase; MCP-1: 2.4-fold increase; pro-MMP1: 5.1-fold increase; MMP-3: 83.6‑fold increase). At equal concentrations, both saturated and unsaturated fatty acids showed similar effects, while responses to FFA were generally stronger for OASF and PsASF than for RASF (e.g. for palmitic acid [10 µM] with RASF / IL-6: 2.8-fold increase; with OASF: 15.2-fold increase; with PsA‑SF: 39.3-fold increase). Pre-incubation of RASF with SSO almost completely abrogated the effect of palmitic acid on IL-8 secretion. However, both intracellular and extracellular TLR4 signaling inhibition blocked the palmitic acid-induced IL-6 secretion of RASF.

Conclusion: The data show that FFA are not only metabolic substrates but also directly contribute to articular inflammation and degradation in various joint diseases. Moreover, the data support the hypothesis that FFA-induced joint destruction is mediated through the innate immune system.

Disclosure:

K. W. Frommer,
None;

A. Schäffler,
None;

S. Rehart,
None;

A. Lehr,
None;

U. Müller-Ladner,
None;

E. Neumann,
None.

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