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E F Morand

Publications and source records attributed to E F Morand.

At least 19 recordsLinked to original sources
PubMed2006

Macrophage migration inhibitory factor and glucocorticoid sensitivity.

Glucocorticoids (GCs) are widely used in the treatment of inflammatory diseases including rheumatoid arthritis (RA). Treatment with GC is associated with significant dose-dependent side-effects. The pro-inflammatory cytokine macrophage migration inhibitory factor (MIF) has emerged in recent years as a candidate factor which could regulate GC sensitivity. MIF is induced by GC, and is able to override anti-inflammatory actions of GCs. In this review, we summarize the pro-inflammatory actions of MIF with respect to RA, describe the interactions between MIF and GC and examine new evidence, which identifies MIF as a specific target for steroid sparing.

Animals↗
PubMed2005

New therapeutic target in inflammatory disease: macrophage migration inhibitory factor.

The cytokine macrophage migration inhibitory factor (MIF) participates in fundamental events in innate and adaptive immunity. The profile of activities of MIF in vivo and in vitro is strongly suggestive of a role for MIF in the pathogenesis of many inflammatory diseases, including rheumatoid arthritis (RA), and hence antagonism of MIF is suggested as a potential therapeutic strategy in inflammatory disease. The best developed case for therapeutic antagonism of MIF is in RA. In RA, MIF is abundantly expressed in serum and synovial tissue. MIF induces synovial expression of key pro-inflammatory genes, regulates the function of endothelial cells and leucocytes, and is implicated in the control of synoviocyte proliferation and apoptosis via direct effects on the expression of the tumour suppressor protein p53. In animal models of RA, anti-MIF antibodies or genetic MIF deficiency are associated with significant inhibition of disease. A similar case has been made, for example using MIF-deficient mice, in models of atheroma, colitis, multiple sclerosis and other inflammatory diseases. The relationship with p53 also means MIF may be important in the link between inflammatory disease and cancer, such as is seen in RA or colitis. MIF also has a unique relationship with glucocorticoids, in that despite antagonizing their effects, the expression of MIF is in fact induced by glucocorticoids. Thus, MIF functions as a physiological counter-regulator of the anti-inflammatory effects of glucocorticoids. This may be entrained by selective activation of mitogen-activated protein kinases rather than nuclear factor kappa B. Therapeutic MIF antagonism may therefore provide a specific means of 'steroid sparing'. Exploitation of antibody, soluble receptor or small molecule technologies may soon lead to the ability to test in the clinic the importance of MIF in human inflammatory diseases.

Animals↗
PubMed2002

Macrophage migration inhibitory factor in rheumatoid arthritis: clinical correlations.

OBJECTIVE: Cytokines play an important role in the pathology of rheumatoid arthritis (RA). Macrophage migration inhibitory factor (MIF) is a cytokine with a broad spectrum of actions, including induction of monocyte tumour necrosis factor alpha (TNF-alpha). Evidence of the expression and proinflammatory activity of MIF has recently been demonstrated in RA synovium and in animal models of RA. We wished to assess the relationship between MIF expression in synovium and clinical disease. METHODS: Computer-assisted analysis of the cytokine content of arthroscopically obtained biopsies of RA synovium, using paired samples from eight patients with active and inactive/treated disease, was compared with documented clinical parameters. RESULTS: Synovial MIF immunostaining correlated strongly with disease activity as measured by CRP concentration. Reductions in clinical disease parameters, including CRP, tender and swollen joint counts, were accompanied by significant reductions in synovial MIF. Synovial TNF-alpha, transforming growth factor beta (TGF-beta) and interleukin (IL) 10 also showed a significant reduction in association with reduced disease activity, while IL-1 beta and IL-1 receptor agonist did not. CONCLUSION: The correlation of synovial MIF with disease activity corroborates existing evidence of the role of this cytokine in RA. The demonstration that only MIF and TNF-alpha show significant variation in synovial cytokine content with clinical remission suggests that MIF is an important member of the cytokine hierarchy in RA.

Aged↗
PubMed2001

Regulation of synoviocyte phospholipase A2 and cyclooxygenase 2 by macrophage migration inhibitory factor.

OBJECTIVE: Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine with known actions in macrophage and T cell activation. MIF also has the unique capacity to reverse the inhibitory effects of glucocorticoids on these cells. We have recently demonstrated MIF expression in human rheumatoid arthritis (RA) synovium and cultured fibroblast-like synoviocytes (FLS), as well as the ability of FLS-derived MIF to induce monocyte release of tumor necrosis factor alpha. We investigated the effects of MIF on aspects of RA FLS activation, including the induction of phospholipase A2 (PLA2) and cyclooxygenase (COX). METHODS: PLA2 activity was measured by 3H-arachidonic acid released from treated FLS supernatants. COX activity was measured by prostaglandin E2 enzyme-linked immunosorbent assay. Cytosolic PLA2 (cPLA2) and COX-2 messenger RNA (mRNA) were determined using semiquantitative reverse transcriptase-polymerase chain reaction. RESULTS: Constitutive PLA2 activity was detected in RA FLS. Recombinant human MIF up-regulated PLA2 activity (P < 0.01) and cPLA2 mRNA expression, but had no effect on secretory PLA2. Recombinant human MIF up-regulated COX activity (P < 0.05) and COX-2 mRNA, but had no observable effect on COX-1. Interleukin-1beta (IL-1beta) significantly up-regulated PLA2 activity (P < 0.005) and cPLA2 mRNA expression while anti-MIF monoclonal antibody (mAb) significantly inhibited this IL-1beta-induced PLA2 activity (P < 0.02). Anti-MIF mAb significantly reduced IL-1beta-induced COX activity (P < 0.05) and COX-2 mRNA expression. CONCLUSION: MIF exerts a proinflammatory effect on key aspects of RA FLS activation. That anti-MIF mAb inhibited IL-1beta up-regulation of FLS indicates an additional cofactor role for MIF in IL-1beta-induced FLS activation. These data suggest that MIF antagonism has important therapeutic potential in RA.

Antibodies, Blocking↗
PubMed2001

Role of macrophage migration inhibitory factor (MIF) in murine antigen-induced arthritis: interaction with glucocorticoids.

(MIF) is a broad-spectrum proinflammatory cytokine implicated in human rheumatoid arthritis. The synthesis of MIF by synovial cells is stimulated by glucocorticoids, and previous studies suggest that MIF antagonizes the anti-inflammatory effects of glucocorticoids. This has not been established in a model of arthritis. We wished to test the hypothesis that MIF can act to reverse the anti-inflammatory effects of glucocorticoids in murine antigen-induced arthritis (AIA). Cutaneous DTH reactions and AIA were induced by intradermal injection and intra-articular injection, respectively, of methylated bovine serum albumin in presensitized mice. Animals were treated with anti-MIF MoAbs, recombinant MIF, and/or dexamethasone (DEX). Skin thickness of DTH reactions was measured with callipers and arthritis severity was measured by blinded quantitative histological assessment of synovial cellularity. Cutaneous DTH to the disease-initiating antigen was significantly inhibited by anti-MIF MoAb treatment (P < 0.001). AIA was also significantly inhibited by anti-MIF MoAb (P < 0.02). DEX treatment induced a dose-dependent inhibition of AIA, which was significant at 0.2 mg/kg (P < 0.05). MIF treatment reversed the effect of therapeutic DEX on AIA (P < 0.001). DEX also significantly inhibited DTH reactions (P < 0.05) but rMIF had no effect on this effect of DEX. DTH and AIA are MIF-dependent models of inflammation and arthritis. The reversal of glucocorticoid suppression of AIA by MIF supports the concept that MIF is a counter-regulator of glucocorticoid control of synovial inflammation. Although DTH was observed to be MIF-dependent and glucocorticoid-sensitive, rMIF had no reversing effect on the suppression of DTH by glucocorticoids. This suggests that inflammatory processes in specific tissues may respond differently to MIF in the presence of glucocorticoids.

Animals↗
PubMed2001

Hypothalamic-pituitary-adrenal axis regulation of inflammation in rheumatoid arthritis.

The profound anti-inflammatory effects of glucocorticoids in drug therapy are reflected in the effects in vivo of endogenous glucocorticoids produced by the adrenals. The production of adrenal glucocorticoids is driven by the hypothalamus and pituitary, which in turn are responsive to circulating products of the inflammatory response, especially cytokines. That inflammation can drive the production of anti-inflammatory glucocorticoids denotes the hypothalamic-pituitary-adrenal (HPA)-immune axis as a classic negative feedback control loop. Defects in HPA axis function are implicated in susceptibility to, and severity of, animal models of rheumatoid arthritis (RA), and are hypothesized to contribute to the human disease. In this paper, data supporting the concept of the HPA axis as a regulator of the inflammatory response in animal models of arthritis are reviewed, along with data from studies in humans. Taken together, these data support the hypothesis that the HPA axis provides one of the key mechanisms for inhibitory regulation of the inflammatory response. Manipulation of HPA axis-driven endogenous anti-inflammatory responses may provide new methods for the therapeutic control of inflammatory diseases.

Animals↗
PubMed2000

Regulation of macrophage migration inhibitory factor by endogenous glucocorticoids in rat adjuvant-induced arthritis.

OBJECTIVE: To explore the regulation of macrophage migration inhibitory factor (MIF) by endogenous glucocorticoids in adjuvant-induced arthritis (AIA). METHODS: Adrenalectomy or sham operation was performed 2 days prior to adjuvant arthritis induction. Synovial explant supernatant levels of MIF and tumor necrosis factor alpha (TNFalpha) were measured by enzyme-linked immunosorbent assay (ELISA). Synovial MIF immunostaining was detected by 3-layer immunohistochemistry. Serum MIF levels were measured by Western blotting. Pituitary MIF release was measured by ELISA. Anti-MIF monoclonal antibody (mAb) or isotype-matched control antibody was administered to adrenalectomized (ADX) animals throughout AIA development. RESULTS: Compared with sham operation, adrenalectomy was associated with significant exacerbation of clinical disease parameters (P < 0.05). Adrenalectomy was associated with significantly reduced levels of synovial MIF, but not TNFalpha. In contrast, adrenalectomy was associated with increased serum MIF levels. Concomitant increased pituitary MIF levels were observed in ADX rats, consistent with the pituitary being the principal source of this increase. The administration of specific anti-MIF mAb conferred 100% protection from lethality during arthritis development and decreased arthritis disease expression. CONCLUSION: These findings provide the first in vivo confirmation of the observation that endogenous glucocorticoids are involved in the regulation of MIF in a site of inflammation, and that local and systemic MIF production are differentially regulated in this setting. The reversal of disease in ADX rats by anti-MIF mAb suggests that balance between glucocorticoids and MIF may influence the expression of inflammatory disease.

Adrenalectomy↗
PubMed2000

Annexin I surface binding sites and their regulation on human fibroblast-like synoviocytes.

OBJECTIVE: Annexin I is a glucocorticoid-inducible protein whose expression in rheumatoid synovium and inhibitory actions in animal models of arthritis suggests its involvement in human arthritis. The present study explored the potential for annexin I to mediate its antiinflammatory actions via specific cell-surface binding sites on human fibroblast-like synoviocytes (FLS). METHODS: Annexin I binding sites on cultured FLS from patients with osteoarthritis (OA) and rheumatoid arthritis (RA) were determined by ligand-binding flow cytometry. Phospholipase A2 (PLA2) activity was determined by arachidonic acid release. RESULTS: FLS exhibited saturable, concentration-dependent cell-surface annexin I binding, with >99% of the OA FLS exhibiting binding at an annexin I concentration of 10 microM. Annexin I binding of RA FLS was significantly lower than that of OA FLS. FLS annexin I binding sites were not affected by elastase or a specific elastase inhibitor, and elastase release did not differ between RA and OA cells. In contrast, collagenase significantly increased annexin I binding sites on OA FLS and approached a significant effect on RA FLS. Tumor necrosis factor alpha increased annexin I binding sites on OA and RA FLS. Similarly, interleukin-1beta significantly increased annexin I binding on OA FLS; but the increased binding on RA FLS was not significant. Dexamethasone exerted no significant effect on OA or RA FLS annexin I binding sites. Treatment of RA FLS with an annexin I N-terminal peptide significantly inhibited RA FLS PLA2 activity. CONCLUSION: This is the first description of the expression, regulation, and function of cell surface annexin I binding sites on FLS. Reduced annexin I binding sites in RA FLS may impair the sensitivity of certain proinflammatory events to glucocorticoids.

Annexin A1↗
PubMed2000

Endogenous glucocorticoids modulate experimental anti-glomerular basement membrane glomerulonephritis.

The influence of endogenous glucocorticoids (GC) on glomerular injury was studied in a rat model of heterologous anti-glomerular basement membrane (GBM) glomerulonephritis (GN). Sprague-Dawley rats underwent adrenalectomy (ADX) or sham-operation 3 days prior to i.v. administration of both nephritogenic (100 microgram/g) and subnephritogenic (50 microgram/g) doses of sheep anti-rat GBM globulin. Administration of a subnephritogenic dose of anti-GBM globulin resulted in GN in adrenalectomized animals only. Similarly, ADX performed prior to administration of anti-GBM in the nephritogenic dose range resulted in exacerbation of GN compared with sham-operated animals (24 h protein excretion: 190.8 +/- 32.8 versus 42.5 +/- 2.6 mg/24 h; P < 0.005). In ADX animals receiving subnephritogenic doses of anti-GBM injury was manifested by abnormal proteinuria (62.7 +/- 5.8 mg/24 h), accumulation of neutrophils which peaked at 6 h (7.2 +/- 1.37 neutrophils per glomerular cross-section (neut/gcs)) and macrophage accumulation in glomeruli at 24 h (6.8 +/- 1.2 macrophages/gcs). Sham-adrenalectomized animals given the same dose of anti-GBM globulin developed minimal or no glomerular injury: urinary protein excretion (8.7 +/- 1.5 mg/24 h, P < 0.001); neutrophils (0.2 +/- 0.04 neutrophils/gcs, P < 0.001); macrophages (1.2 +/- 0.5 macrophages/gcs, P < 0.001). The increased cellular recruitment to glomeruli in adrenalectomized animals was associated with glomerular endothelial P-selectin expression. P-selectin expression was not detected in sham-operated rats after anti-GBM injection. Complement deposition in glomeruli was minimal in both groups. Physiologic GC replacement of ADX rats receiving subnephritogenic-dose anti-GBM reversed the observed susceptibility to GN development, with urinary protein excretion (7.8 +/- 1.12, P < 0.005) and no detectable P-selectin expression or leucocyte accumulation in glomeruli. These results suggest that endogenous GC modulate heterologous anti-GBM nephritis in rats and that this may be attributable, in part, to regulation of P-selectin expression.

Adrenalectomy↗
PubMed2000

Annexin I and dexamethasone effects on phospholipase and cyclooxygenase activity in human synoviocytes.

Annexin I is a glucocorticoid-induced mediator with anti-inflammatory activity in animal models of arthritis. We studied the effects of a bioactive annexin I peptide, ac 2-26, dexamethasone (DEX), and interleukin-1beta (IL-1beta) on phospholipase A2 (PLA2) and cyclooxygenase (COX) activities and prostaglandin E2 (PGE2) release in cultured human fibroblast-like synoviocytes (FLS). Annexin I binding sites on human osteoarthritic (OA) FLS were detected by ligand binding flow cytometry. PLA2 activity was measured using 3H-arachidonic acid release, PGE2 release and COX activity by ELISA, and COX2 content by flow cytometry. Annexin I binding sites were present on human OA FLS. Annexin I peptide ac 2-26 exerted a significant concentration-dependent inhibition of FLS constitutive PLA2 activity, which was reversed by IL-1beta. In contrast, DEX inhibited IL-1beta-induced PLA2 activity but not constitutive activity. DEX but not annexin I peptide inhibited IL-1beta-induced PGE2 release. COX activity and COX2 expression were significantly increased by IL-1beta. Annexin I peptide demonstrated no inhibition of constitutive or IL-1beta-induced COX activity. DEX exerted a concentration-dependent inhibition of IL-1beta-induced but not constitutive COX activity. Uncoupling of inhibition of PLA2 and COX by annexin I and DEX support the hypothesis that COX is rate-limiting for PGE2 synthesis in FLS. The effect of annexin I but not DEX on constitutive PLA2 activity suggests a glucocorticoid-independent role for annexin I in autoregulation of arachidonic acid production. The lack of effect of annexin I on cytokine-induced PGE2 production suggests PGE2-independent mechanisms for the anti-inflammatory effects of annexin I in vivo.

Animals↗
PubMed2000

Corticosteroids in the treatment of rheumatologic diseases.

The year 2000 marks the fiftieth anniversary of the awarding of the Nobel Prize for Medicine to Hench, Kendall, and Reichstein for their discovery of glucocorticoid treatment of rheumatic diseases. The efficacy and toxicity of glucocorticoids has remained a matter of contention ever since, with debate continuing over their place in the therapeutic armamentarium of rheumatologists. Few if any rheumatologists would not prescribe glucocorticoids, however, and review of new data on their use, efficacy, and toxicity remains topical. Perceived advances in the ability to manage osteoporosis arising from glucocorticoid use has allowed focus to shift onto other toxicities, including vascular disease, but important advances in our understanding of the mechanism of action of glucocorticoids are still lacking.

Bone and Bones↗
PubMed1999

Inhibitory effect of annexin I on synovial inflammation in rat adjuvant arthritis.

OBJECTIVE: Annexin I is an endogenous antiinflammatory mediator, expressed in rheumatoid arthritis (RA) synovium, the contribution of which to autoregulation of the synovial inflammatory response has not been examined in models of RA. We investigated the antiinflammatory role of annexin I in rat adjuvant arthritis. METHODS: Rats with adjuvant-induced arthritis (AIA) were treated with a specific anti-annexin I monoclonal antibody (mAb), isotype control IgG, and/or dexamethasone. Clinical outcomes and synovial synthesis of tumor necrosis factor alpha (TNFalpha), prostaglandin E2 (PGE2), and nitric oxide were examined, and annexin I expression was assessed by flow cytometry and reverse transcription-polymerase chain reaction. RESULTS: Anti-annexin I mAb reversed the effects of dexamethasone on the clinical features of AIA and exacerbated AIA in the absence of exogenous glucocorticoid. Clinical exacerbation of AIA by anti-annexin I mAb was accompanied by significantly increased synovial TNFalpha and PGE2, suggesting that annexin I tonically inhibits the production of these mediators. Anti-annexin I mAb treatment was associated with significantly reduced leukocyte intracellular annexin I, despite increased annexin I messenger RNA expression, consistent with a depletion effect of extracellular mAb via the cell surface. CONCLUSION: Annexin I is a key endogenous inhibitory mediator of arthritis via mechanisms that include inhibition of cytokine and effector molecule production. Moreover, a synthesis-independent depletion of intracellular annexin I by extracellular antibody supports the hypothesis that externalization of annexin I is involved in its mode of action.

Animals↗
PubMed1999

Macrophage migration inhibitory factor in rheumatoid arthritis: evidence of proinflammatory function and regulation by glucocorticoids.

OBJECTIVE: Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine whose involvement in tumor necrosis factor alpha (TNFalpha) synthesis and T cell activation suggests a role in the pathogenesis of rheumatoid arthritis (RA). Antagonism of MIF is associated with marked inhibition of animal models of RA. Uniquely, MIF is inducible by low concentrations of glucocorticoids. We sought to investigate the expression of MIF in RA synovial tissue. METHODS: MIF was demonstrated in human RA synovium by immunohistochemistry, flow cytometry, enzyme-linked immunosorbent assay (ELISA), and reverse transcription-polymerase chain reaction (RT-PCR). Regulation of MIF expression was investigated by treatment of cultured fibroblast-like synoviocytes (FLS) with interleukin-1beta (IL-1beta), TNFalpha, or interferon-gamma (IFNgamma), and dexamethasone (DEX). Mononuclear cell TNFalpha release after exposure to FLS-conditioned medium was measured by ELISA. RESULTS: MIF was present in RA synovial lining CD14+ macrophages and FLS. Constitutive MIF messenger RNA (mRNA) expression was demonstrated by RT-PCR of RNA from unstimulated cultured RA FLS, which also released abundant MIF. Serum, synovial fluid, and FLS intracellular MIF were significantly higher in RA patients than in controls. Synoviocyte MIF was not increased by IL-1beta, TNFalpha, or IFNgamma. In contrast, DEX 10(-7)M significantly reduced synoviocyte MIF, while DEX 10(-10)-10(-12)M induced a significant increase in MIF and MIF mRNA. Peripheral blood mononuclear cell TNFalpha release was induced by culture in RA FLS-conditioned medium, and this induction was significantly abrogated by monoclonal anti-MIF antibody, suggesting that MIF is an upstream regulator of TNFalpha release. CONCLUSION: These data represent the first demonstration of the cytokine MIF in human autoimmune disease and suggest MIF as a potential therapeutic target in RA.

Aged↗
PubMed1999

Glucocorticoid regulation of inflammation: the plot thickens.

While glucocorticoids are widely used in the suppression of immune-inflammatory diseases, much remains unknown about the contribution of endogenous adrenal glucocorticoids to inflammatory regulation. It is now well understood that glucocorticoids are increased by inflammatory stress and provide for responsive limitation of inflammation. It is self-evident that the immune response in healthy animals takes place in a milieu characterised by background levels of glucocorticoids. It is less well appreciated, however, that basal levels of glucocorticoids may in fact be a requirement for a normal immune response. In fact, extensive data exist supporting the hypothesis that glucocorticoids interact with the immune-inflammatory system in a biphasic, concentration dependent fashion. No mechanistic explanation for this apparent paradox has previously existed. Recently, the cytokine macrophage migration inhibitory factor (MIF), while possessing pleiotropic pro-inflammatory properties, has been demonstrated to be glucocorticoid-inducible. This observation has the potential to explain key aspects of the biphasic regulation of inflammatory response by endogenous glucocorticoids.

Animals↗
PubMed1999

Three year follow-up of body composition changes in pre-menopausal women with systemic lupus erythematosus.

OBJECTIVES: To measure the change in body composition in a pre-menopausal female systemic lupus erythematosus (SLE) population over 3 yr, and to identify predictors of change in body composition including the effects of disease-, corticosteroid (CS)- and patient-related variables. METHODS: All 55 pre-menopausal females with SLE who participated in a cross-sectional study of body composition in 1994 were invited to undergo interview, examination, medical record review, and body composition assessment by dual-energy X-ray absorptiometry (DXA). RESULTS: Twenty-eight subjects participated with a mean (S.E.M.) age of 34.4 (1.6) yr, duration of SLE of 6.8 (0.8) yr and mean (range) time to follow-up of 3.2 (2.9-3.4) yr. Seventeen subjects were exposed to CS during the study period with a mean (range) daily dose of prednisolone of 12.0 (2.8-22.9) mg. There was a significant increase in body mass index (BMI) (24.53+/-0.83 vs 25.37+/-1.04, P = 0.03) and fat-free mass (41.04+/-0.83 vs 41.53+/-0.92, P = 0.05) over the 3 yr period. Univariate analysis revealed that change in fat-free mass was significantly associated with change in total body bone mineral density (BMD) (P = 0.03). Stepwise multiple linear regression analysis revealed a significant independent association of disease activity with increases in both BMI (r2 = 0.41, P = 0.006) and fat mass (r2 = 0.39, P = 0.007), and of exercise and Modified Health Assessment Questionnaire with an increase in fat-free mass (r2 = 0.51, P = 0.007). Age at SLE diagnosis and smoking were significant independent predictors for loss of total body BMD, while CS duration was predictive of an increase in total body BMD (r2 = 0.80, P < 0.0001). CONCLUSION: In this SLE population, disease activity was predictive of deleterious changes in body composition, including increases in BMI and fat mass. Patient-related variables were also important predictors of body composition change with exercise independently predicting an increase in fat-free mass, and smoking predictive of loss of total body BMD. In contrast, CS-related variables were not found to have harmful effects on body composition. Change in fat-free mass, and not fat mass, was predictive of change in total body BMD.

Absorptiometry, Photon↗
PubMed1998

Involvement of macrophage migration inhibitory factor in the evolution of rat adjuvant arthritis.

OBJECTIVE: Recent studies have established an essential role for macrophage migration inhibitory factor (MIF) in T cell and macrophage activation, both of which are characteristics of rat adjuvant arthritis. This study investigated the role of MIF in early adjuvant arthritis. METHODS: MIF was detected in rat synovium by immunohistochemistry and enzyme-linked immunosorbent assay using specific monoclonal antibodies (MAb). Anti-MIF MAb treatment was administered, and the effects on clinical aspects of adjuvant arthritis were assessed. RESULTS: MIF was absent from normal rat synovium prior to adjuvant injection, but was detectable on day 4 after injection (6 days before the onset of clinical disease) and was colocalized with ED-1+ macrophages throughout the evolution of the disease. Levels of MIF were increased in established adjuvant arthritis sera, and adjuvant arthritis synovial macrophages released MIF at a mean +/- SEM concentration of 607.9 +/- 201.5 pg/ml. Anti-MIF treatment led to profound, dose-dependent inhibition of the adjuvant arthritis clinical score, paw swelling, and synovial lavage leukocyte numbers (P < 0.001), and also resulted in reduced synovial macrophage and T cell accumulation. CONCLUSION: These findings demonstrate an important role for MIF in the evolution of rat adjuvant arthritis.

Animals↗
PubMed1998

Urinary excretion of the pyridinium cross-links of collagen in systemic lupus erythematosus.

The aim of this study was to measure the urinary excretion of the pyridinium cross-links of collagen and to determine their usefulness as markers of reduced bone mineral density in systemic lupus erythematosus (SLE). All female SLE patients managed at a single centre were invited to participate in a cross-sectional study of urinary pyridinium cross-links excretion (HPLC), bone mineral density (DXA), and SLE-related variables. Ninety-one women with SLE were studied, 35 of whom were postmenopausal. Pyridinoline/Creatinine (Pyd/Cr) and deoxypyridinoline/Cr (Dpd/Cr) levels in postmenopausal women were significantly increased compared with premenopausal values (p = 0.010 and p = 0.004, respectively). Univariate linear regression analysis revealed a significant association of Dpd/Cr with reduced femoral neck and lumbar spine BMD (p = 0.001, p<0.001), and of Pyd/Cr with reduced femoral neck BMD (p = 0.020). In addition, the association of Pyd/Cr with reduced lumbar spine BMD approached significance (p = 0.055). Stepwise multiple linear regression analysis adjusting for other variables confirmed a significant association of Dpd/Cr with reduced lumbar spine BMD (p = 0.006), and a significant association of both Pyd/Cr and Dpd/Cr with postmenopausal status (p = 0.003, p<0.001). It was concluded that in this SLE population, the urinary excretion of Dpd/Cr was a useful marker of reduced BMD at the lumbar spine. Menopausal status was a major predictor of cross-links excretion in SLE.

Absorptiometry, Photon↗