Positive correlation between levels of IL-1 or IL-2 and 1,25(OH)2D/25-OH-D ratio in synovial fluid of patients with rheumatoid arthritis

doi:10.1016/S0024-3205(97)00602-4

Life Sciences

Volume 61, Issue 10, 1 August 1997, Pages 977-985

https://doi.org/10.1016/S0024-3205(97)00602-4 Get rights and content

Abstract

The present study determined the levels in synovial fluid (SF) of vitamin D metabolites (1,25-dihydroxyvitamin D (1,25(OH)₂D), 24,25-dihydroxyvitamin D (24,25(OH)₂D) and 25-hydroxyvitamin D (25-OH-D)), and of the cytokines. We evaluated SF from 21 patients with rheumatoid arthritis (RA) and 6 patients with osteoarthritis (OA). The levels of vitamin D metabolites in SF, as determined by two different extraction methods, were significantly correlated (p < 0.05, n = 7). The levels of 3 vitamin D metabolites were significantly higher in the RA SF than in OA SF (p < 0.05). The ratio of 1,25(OH)₂D/25-OH-D in RA SF, which is presumed to reflect the activity of 25-OH-D-1-hydroxylase (1-OH-ase), was positively correlated with the levels of interleukin-1α (IL-1α), IL-1β, and IL-2 in such SF, and was significantly higher than that in sera from RA patients. This suggests an important role for these cytokines in the activation of 1-OH-ase in RA synovium. The ratio of 24,25(OH)₂D/25-OH-D, which is presumed to reflect 25-OH-D-24-hydroxylase (24-OH-ase) activity, was significantly correlated with 1,25(OH)₂D levels only in RA SF, but not in sera from RA patients, suggesting a local regulation of vitamin D metabolism that 1,25-(OH)₂D induces 24-OH-ase as in other target cells. Our observations suggested that 1,25(OH)₂D and 24,25(OH)₂D are produced locally from 25-OH-D in RA synovium, and that the syntheses of 1,25(OH)₂D and 24,25(OH)₂D may be affected by $IL-1 IL-2$ and 1,25(OH)₂D in RA SF, respectively.

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Rheumatoid arthritis (RA) is a complex autoimmune inflammatory rheumatic disease characterized by an imbalance between immunological reactivity and immune tolerance. Regulatory T cells (Tregs), which play a crucial role in controlling ongoing autoimmunity and maintaining peripheral tolerance, have shown great potential for the treatment of autoimmune inflammatory rheumatic diseases such as RA. This review aims to provide an updated summary of the latest insights into Treg-targeting techniques in RA. We focus on current therapeutic strategies for targeting Tregs based on discussing their subsets, surface markers, suppressive function, and signaling pathways in RA.
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By contrast, previous analysis of 1,25(OH)2D3 in RA patients reported similar [44], or modestly suppressed [43] concentrations in SF relative to serum. One possible explanation for significantly lower levels of SF 1,25(OH)2D3 in the current study is the use of more reliable LC-MS/MS technology for quantification of 1,25(OH)2D3, compared to the relatively non-specific radioreceptor [44] or radioimmunoassays [43] used to measure 1,25(OH)2D3 in the previous studies. Previous studies also reported strong correlation between serum and SF 1,25(OH)2D3, and between SF 25(OH)D3 and SF 1,25(OH)2D3 [43], which we did not observe in the current study.
Vitamin D-deficiency has been linked to inflammatory diseases including rheumatoid arthritis (RA). Studies to date have focused on the impact of serum 25-hydroxyvitamin D3 (25(OH)D3), an inactive form of vitamin D, on RA disease activity and progression. However, anti-inflammatory actions of vitamin D are likely to be mediated at sites of RA disease, namely the inflamed joint, and may involve other vitamin D metabolites notably the active form of vitamin D, 1,25-dihydroxyvitamin D3 (1,25(OH)₂D3). In the current study serum and synovial fluid samples from n = 20 patients with persistent RA and n = 7 patients with reactive arthritis (ReA) were analysed for multiple vitamin D metabolites. Serum data for RA and ReA patients were compared to healthy controls (HC). There was no significant difference between RA or ReA patients relative to HC for 25(OH)D3, 24,25(OH)₂D3, 1,25(OH)₂D3 or 25(OH)D2. However, 3-epi-25(OH)D3 was significantly lower in RA and ReA patients compared to HC (p < 0.05). All vitamin D metabolites, apart from 25(OH)D2, were lower in SF compared to serum, and SF 1,25(OH)₂D3 was unquantifiable in 13/20 RA and 4/7 ReA samples. SF 25(OH)D3, 3-epi-25(OH)D3 and DBP correlated inversely with swollen joint score, and serum 25(OH)D2 and SF DBP correlated directly with C-reactive protein levels. These data indicate that serum 25(OH)D3 provides only limited insight into the role of vitamin D in RA. Alternative serum metabolites such as 3-epi-25(OH)₂D3, and SF metabolites, notably lack of SF 1,25(OH)₂D3, may be more closely linked to RA disease severity and progress.
Vitamin D and inflammation
2011, Revue du Rhumatisme (Edition Francaise)
La 1,25-dihydroxyvitamine D3 (1,25(OH)₂D3) est connue pour son effet endocrine sur l’homéostasie calcique. De manière plus récente, a été découverte une action immunomodulatrice paracrine ou autocrine liée à la synthèse locale de 1,25(OH)₂D3 par les cellules du système immunitaire, qui expriment le récepteur de la vitamine D (VDR) et les enzymes nécessaires à son métabolisme (1α-, 25- et 24-hydroxylases). Ces effets immunomodulateurs, mis en évidence dans les modèles animaux et les expériences de culture cellulaire, s’exercent de manière directe et indirecte, concernent les lymphocytes T et B ainsi que les cellules présentatrices d’antigène (cellules dendritiques et macrophages). Ils interviennent dans l’immunité innée et adaptative. L’effet global est un switch d’une réponse Th1/Th17 vers un profil Th2/Treg. Ces effets immunomodulateurs de la vitamine D pourraient expliquer la relation épidémiologique entre le statut vitaminique D et de nombreuses pathologies auto-immunes et inflammatoires suggérée par des études observationnelles (dans la polyarthrite rhumatoïde, le lupus, les entéropathies inflammatoires, le diabète de type 1, mais aussi les infections, cancers, rejets de greffes et maladies cardiovasculaires). Un effet thérapeutique de la supplémentation en vitamine D a également été mis en évidence dans les modèles animaux correspondant à ces pathologies. Ainsi, la vitamine D est un enjeu majeur de santé publique et pourrait représenter un espoir thérapeutique dans les maladies dysimmunitaires.
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Joint fluid macrophages can produce 1,25(OH)2D3. High levels of vitamin D metabolites have been found in joint fluid from patients with arthritis [38], suggesting a pathophysiological role for 1,25(OH)2D3 in rheumatoid lesions. The prevalence of IBD is higher in areas that receive less sunlight, such as the northernmost parts of Europe and America [39].
Calcitriol, or 1,25-dihydroxyvitamin D3 (1,25(OH)₂D3) is a well-known endocrine regulator of calcium homeostasis. More recently, local calcitriol production by immune cells was shown to exert autocrine or paracrine immunomodulating effects. Immune cells that produce calcitriol also express the vitamin D receptor (VDR) and the enzymes needed to metabolize vitamin D3 (1α-, 25-, and 24-hydroxylases). Studies of animal models and cell cultures showed both direct and indirect immunomodulating effects involving the T cells, B cells, and antigen-presenting cells (dendritic cells and macrophages) and affecting both innate and adaptive immune responses. The overall effect is a switch from the Th1/Th17 response to the Th2/Treg profile. The immunomodulating effects of vitamin D may explain the reported epidemiological associations between vitamin D status and a large number of autoimmune and inflammatory diseases. Such associations have been suggested by observational studies not only in rheumatoid arthritis, lupus, inflammatory bowel disease, and type 1 diabetes; but also in infections, malignancies, transplant rejection, and cardiovascular disease. In animal models for these diseases, vitamin D supplementation has been found to produce therapeutic effects. Thus, vitamin D is a key focus for public health efforts and may hold promise for the treatment of dysimmune diseases.
Serum levels of 1,25-dihydroxyvitamin D, 24,25-dihydroxyvitamin D, and 25-hydroxyvitamin D in nondialyzed patients with chronic renal failure
1999, Kidney International
Serum levels of 1,25-dihydroxyvitamin D, 24,25-dihydroxyvitamin D, and 25-hydroxyvitamin D in nondialyzed patients with chronic renal failure.
In patients with chronic renal failure (CRF), abnormalities in vitamin D metabolism are known to be present, and several factors could contribute to the abnormalities.
We measured serum levels of three vitamin D metabolites, 1,25(OH)₂D, 24,25(OH)₂D and 25(OH)D, and analyzed factors affecting their levels in 76 nondialyzed patients with CRF (serum creatinine> 1.6 and < 9.0 mg/dl), 37 of whom had diabetes mellitus (DM-CRF) and 39 of whom were nondiabetic (nonDM-CRF).
Serum levels of 1,25(OH)₂D were positively correlated with estimated creatinine clearance (C_Cr; r = 0.429; P < 0.0001), and levels of 24,25(OH)₂D were weakly correlated with C_Cr (r = 0.252, P < 0.05); no correlation was noted for 25(OH)D. Serum levels of all three vitamin D metabolites were significantly and positively correlated with serum albumin. Although there were no significant differences in age, sex, estimated C_Cr, calcium and phosphate between DM-CRF and nonDM-CRF, all three vitamin D metabolites were significantly lower in DM-CRF than in nonDM-CRF. To analyze factors influencing vitamin D metabolite levels, we performed multiple regression analyses. Serum 25(OH)D levels were significantly and independently associated with serum albumin, presence of DM and serum phosphate (R² = 0.599; P < 0.0001). 24,25(OH)₂D levels were significantly and strongly associated with 25(OH)D (β; = 0.772; R² = 0.446; P < 0.0001). Serum 1,25(OH)₂D levels were significantly associated only with estimated C_Cr (R² = 0.409; P < 0.0001).
These results suggest that hypoalbuminemia and the presence of DM independently affect serum 25(OH)D levels, probably via diabetic nephropathy and poor nutritional status associated with diabetes, and that 25(OH)D is actively catalyzed to 24,25(OH)₂D in CRF, probably largely via extrarenal 24-hydroxylase. Serum levels of 1,25(OH)₂D were significantly affected by the degree of renal failure. Thus, this study indicates that patients with CRF, particularly those with DM, should receive supplements containing the active form of vitamin D prior to dialysis.
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Positive correlation between levels of IL-1 or IL-2 and 1,25(OH)2D/25-OH-D ratio in synovial fluid of patients with rheumatoid arthritis

Abstract

Metabolism

Steroids

Blood

Arch. Biochem. Biophys.

Biochim. Biophys. Acta

J. Immunol. Methods

Arthritis Rheum.

J. Clin. Invest.

Arthritis Rheum.

J. Immunol.

J. Clin. Invest.

Biochem. Biophys. Res. Commun.

J. Clin. Endocrinol. Metab.

J. Cell. Physiol.

N. Engl. J. Med.

Immunol. Lett.

Nephron

J. Cell. Biochem.

Positive correlation between levels of IL-1 or IL-2 and 1,25(OH)₂D/25-OH-D ratio in synovial fluid of patients with rheumatoid arthritis