Sphingosine 1‐phosphate/sphingosine 1‐phosphate receptor 1 signaling in rheumatoid synovium: Regulation of synovial proliferation and inflammatory gene expression

While inflammatory cytokines are well-recognized critical factors for the induction of cyclooxygenase-2 (COX-2) in activated fibroblast-like synovial cells, the roles of biologically active components other than inflammatory cytokines in synovial fluid remain unknown. Herein, we assessed the role of lysophosphatidic acid (LPA), a pleiotropic lipid mediator, in COX-2 induction using synovial fluid of patients with rheumatoid arthritis (RA) in fibroblast-like RA synovial cells. Synovial fluid from RA patients stimulated COX-2 induction, which was associated with prostaglandin E2 production, in RA synovial cells. The synovial fluid-induced actions were inhibited by Gi/o protein inhibitor pertussis toxin and LPA receptor antagonist 3-(4-[4-([1-(2-chlorophenyl)ethoxy]carbonyl amino)-3-methyl-5-isoxazolyl] benzylsulfanyl) propanoic acid (Ki16425). In fact, LPA alone significantly induced COX-2 expression and enhanced IL-1α- or IL-1β-induced enzyme expression in a manner sensitive to pertussis toxin and Ki16425. RA synovial cells abundantly expressed LPA1 receptor compared with other LPA receptor subtypes. Moreover, synovial fluid contains a significant amount of LPA, an LPA-synthesizing enzyme autotaxin, and its substrate lysophosphatidylcholine. In conclusion, LPA existing in synovial fluid plays a critical role in COX-2 induction in collaboration with inflammatory cytokines in RA synovial cells. Ki16425-sensitive LPA receptors may be therapeutic targets for RA.

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“…Consistent with a previous report (28), a lipid mediator, S1P, stimulated COX-2 expression in a time- (Fig. 2A) and dose- (Fig.…”

Section: Induction Of Cox-2 Expression By Lpa and S1psupporting

confidence: 93%

“…In a recent study (28), S1P was shown to enhance TNF-␣-and IL-1␤-induced COX-2 expression. In contrast to the previous study (28), however, we failed to detect a significant amount of S1P in the synovial fluid by our assay method.…”

Section: Discussionmentioning

confidence: 92%

Stimulatory Role of Lysophosphatidic Acid in Cyclooxygenase-2 Induction by Synovial Fluid of Patients with Rheumatoid Arthritis in Fibroblast-Like Synovial Cells

Nochi

Tomura

Tobo

et al. 2008

The Journal of Immunology

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“…33,34 S1P has also been shown to induce COX-2 expression, thereby enhancing inflammation. 35,36 This is consistent with findings that S1P/S1P receptor signaling is enhanced in rheumatoid arthritis and may contribute to synovial cell proliferation in this disease, 37 although other studies suggest S1P may not be critical for inflammatory responses. 38 S1P signaling may also be involved in carcinogenesis.…”

Section: S1p Proliferation and Cancersupporting

confidence: 87%

Sphingosine-1-Phosphate Metabolism and Intestinal Tumorigenesis: Lipid Signaling Strikes Again

Oskouian¹,

Saba²

2007

Cell Cycle

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“…Unlike T cells, B cells, etc., mast cells secrete a substantial amount of S1P suggesting it is important for mast cell effector functions. S1P is also highly elevated in the airways of asthmatic individuals (Jolly et al, 2002), and in the joints of arthritic individuals (Kitano et al, 2006). Both asthma and rheumathoid arthritis are inflammatory conditions in which mast cells have been demonstrated to be important effector cells, the latter primarily in a mouse model (Galli, 1997a;Lee et al, 2002).…”

Section: S1p Is An In Vivo Effector Of Mast Cell Functionmentioning

confidence: 99%

Chapter 3 New Insights on Mast Cell Activation via the High Affinity Receptor for IgE

Rivera

Fierro

Olivera

et al. 2008

Advances in Immunology

179

152

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Mast cells are innate immune cells that function as regulatory or effector cells and serve to amplify adaptive immunity. These cells also function in adaptive immunity primarily through cell surface Fc receptors that bind immunoglobulin antibodies. The dysregulation of their adaptive role makes them central players in allergy and asthma. Upon encountering an allergen (antigen), which is recognized by immunoglobulin E (IgE) antibodies bound to the high affinity IgE receptor (FcεRI) expressed on their cell surface, mast cells secrete both preformed and newly synthesized mediators of the allergic response. Blocking of these responses is an objective in therapeutic intervention of allergic diseases. Thus, understanding the mechanisms by which antigens elicit mast cell activation (via FcεRI) holds promise towards identifying therapeutic targets. Here we review the most recent advances in understanding antigen-dependent mast cell activation. Specifically, we focus on the requirements for FcεRI activation; the regulation of calcium responses; co-stimulatory signals in FcεRI-mediated mast cell activation and function; and how genetics influences mast cell signaling and responses. These recent discoveries open new avenues of investigation with therapeutic potential.

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Sphingosine 1‐phosphate/sphingosine 1‐phosphate receptor 1 signaling in rheumatoid synovium: Regulation of synovial proliferation and inflammatory gene expression

Cited by 150 publications

References 44 publications

Stimulatory Role of Lysophosphatidic Acid in Cyclooxygenase-2 Induction by Synovial Fluid of Patients with Rheumatoid Arthritis in Fibroblast-Like Synovial Cells

Stimulatory Role of Lysophosphatidic Acid in Cyclooxygenase-2 Induction by Synovial Fluid of Patients with Rheumatoid Arthritis in Fibroblast-Like Synovial Cells

Sphingosine-1-Phosphate Metabolism and Intestinal Tumorigenesis: Lipid Signaling Strikes Again

Chapter 3 New Insights on Mast Cell Activation via the High Affinity Receptor for IgE

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