Atypical lymphoplasmacytic and immunoblastic proliferation of autoimmune disease : clinicopathologic and immunohistochemical study of 9 cases.

Atypical lymphoplasmacytic immunoblastic proliferation (ALPIB) is a rare lymphoproliferative disorder (LPD) associated with autoimmune disease (AID). To further clarify the clinicopathologic, immunohistological, and genotypic findings of ALPIB in lymph nodes associated with well-documented AIDs, 9 cases are presented. These 9 patients consisted of 4 patients with systemic lupus erythematosus, 3 patients with rheumatoid arthritis, and one case each with Sjögren's syndrome and dermatomyositis. All 9 patients were females aged from 25 to 71 years with a median age of 49 years. Four cases presented with lymphadenopathy as the initial manifestation. In 4 patients, immunosuppressive drugs were administered before the onset of lymph node lesion. However, none of the 9 patients received methotrexate therapy. The present 9 cases were characterized by : (i) prominent lymphoplasmacytic and B-immunoblastic infiltration ; (ii) absence of pronounced arborizing vascular proliferation ; (iii) absence of CD10(+) "clear cells" ; (iv) presence of hyperplastic germinal center in 7 cases ; (v) immunohistochemistry, flow cytometry, and polymerase chain reaction demonstrated a reactive nature of the T- and B-lymphocytes ; and (vi) on in situ hybridization, there were no Epstein-Barr virus -infected lymphoid cells in any of the 9 cases. Overall 5-year survival of our patients was 83%. The combination of clinical, immunophenotypic, and genotypic findings indicated that the present 9 cases can be regarded as having an essentially benign reactive process. Finally, we emphasized that ALPIB should be added to the differential diagnostic problems of atypical LPDs, particularly lymph node lesions of IgG4-related diseases.

Successful treatment of lipoprotein glomerulopathy in a daughter and a mother using niceritrol.

We report two patients, a daughter and a mother, with lipoprotein glomerulopathy (LPG) who were successfully treated with niceritrol. Both patients carried a mutation in the apolipoprotein E (apoE) gene known as ApoE Tokyo/Maebashi. The daughter was found to have proteinuria at the age of 4 years. Four years later, she was diagnosed as having LPG based on a renal biopsy. She was treated with several medications including pravastatin, ethyl icosapentate, enalapril, warfarin and cyclophosphamide, all of which failed to reduce her proteinuria. At the age of 17 years, she exhibited an increase in proteinuria and a decline in renal function, despite ongoing treatment with pravastatin and enalapril. After switching from pravastatin to niceritrol, a marked reduction in the proteinuria and an improvement in renal function were observed. Her mother was found to have proteinuria at the age of 57 years and was diagnosed as having LPG based on a renal biopsy. She was also treated with niceritrol, resulting in an improvement in her proteinuria and renal function. These cases suggest that niceritrol might be a useful therapeutic option for LPG.

Improved management of intradialytic hypotension (IDH) using vitamin E-bonded polysulfone membrane dialyzer.

BACKGROUND: Intradialytic hypotension (IDH) is a common clinical trait in hemodialysis (HD) which is caused by poor biocompatibility of the dialyzer membrane. Aiming to improve IDH, vitamin E-bonded polysulfone dialyzer (VPS-H) was evaluated in a pilot study. METHODS: Eight IDH patients on standard HD were switched from their conventional high-flux dialyzers to VPS-H, and intradialytic blood pressure (BP) was monitored regularly for 10 months. RESULTS: The results showed that hypotension of systolic BP (SBP), diastolic BP (DBP) and pulse pressure (PP) during the session were improved after changing the dialyzer. Notably, almost all the values recorded from 120 minutes into the session until the end of the treatment in the period between the second and tenth month after treatment were significantly different from the corresponding baseline values. Moreover, after 8 to 10 months, the SBP prior to a dialysis session was significantly reduced compared with baseline values. On the other hand, the pulse rate showed no difference throughout the study period. CONCLUSIONS: This study provides early evidence of the beneficial role that vitamin E-bonded dialyzers may have in preventing IDH. Larger controlled trials are needed to confirm this original finding.

Pure red cell aplasia accompanied by autoimmune hemolytic anemia in a patient with type A viral hepatitis.

A rare case of acute hepatitis A associated with autoimmune hemolytic anemia (AIHA) and pure red cell aplasia (PRCA) is reported. A 55-year-old woman consulted a doctor because of common cold-like symptoms and she was referred to our hospital in January 2007. Laboratory findings showed a marked elevation of serum transaminase and total bilirubin levels (AST 9,605 IU/l, ALT 5,546 IU/l and T-bil 4.14 mg/dl), and prolonged prothrombin time, findings which suggested the risk of progression to fulminant hepatitis, and she was treated with plasmapheresis and hemodialysis filtration on the first and second hospital days. She was diagnosed with severe acute hepatitis A based on the elevation of serum IgM anti-hepatitis A virus. On the 20th hospital day, her hemoglobin level began to decrease in spite of improving transaminase levels without any signs of gastrointestinal bleeding. Bilirubin and LDH elevation, haptoglobin decline and a positive direct Coombs test were detected and these findings indicated AIHA complication; however, the reticulocyte count decreased and bone marrow showed marked erythroid hypoplasia so the co-existence of PRCA was diagnosed. After oral prednisolone administration (1 mg/kg/day), her hemolytic anemia rapidly improved.

[Efficacy of steroid pulse therapy in patients with IgA nephropathy and impaired renal function].

OBJECTIVE: In the current study, we evaluated the efficacy of methylprednisolone (MP) pulse therapy in IgA nephropathy (IgAN) patients with established renal function impairment. PATIENTS AND METHODS: We retrospectively analyzed the effect of MP pulse therapy in patients with histologically active IgAN (8 males, 12 females) whose estimated glomerular filtration rate was less than 60 mL/min/1.73 m2 (33.4 +/- 13.1, mean +/- SD). The efficacy of the MP pulse therapy was analyzed by calculating the regression coefficients (dL/mg/month) from the slopes of the 1/serum creatinine (Cr), urine protein/creatinine ratio (g/g x Cr), and the estimated interval from the pulse therapy to dialysis (that is, for Cr to reach 8 mg/dL, as calculated from the slope of 1/Cr) or the actual interval. RESULTS: All patients showed improved regression coefficients (-0.0214 +/- 0.00166 vs. 0.00236 +/- 0.00895, 1 year before vs. after treatment, p < 0.01). The severity of proteinuria decreased significantly from a mean urine protein/creatinine ratio of 2.9 +/- 1.7 before therapy to 1.1 +/- 0.8 (p < 0.01) at 6 months and 0.8 +/- 0.7(p < 0.01) at 12 months after therapy. Although 7 patients underwent dialysis, the average interval from pulse therapy to dialysis was prolonged from an estimated interval of 1.1 +/- 0.9 years to an actual interval of 4.1 +/- 3.5 years. Six patients showed positive regression coefficients at the last observation (4.1 +/- 3.0 years after therapy). The remaining 7 patients who had not undergone dialysis also showed prolongation of the estimated interval from pulse therapy to dialysis of 5.9 +/- 5.1 years before pulse therapy to 25.7 +/- 20.6 years at the final observation (4.9 +/- 3.5 years after therapy). No serious side effects were observed in any of the patients. CONCLUSION: MP pulse therapy can slow the progression of renal deterioration in patients with active IgAN, even in those patients in whom renal function impairment has set in.

Angiotensin II type 1 receptor blockade inhibits the development and progression of HIV-associated nephropathy in a mouse model.

HIV-associated nephropathy (HIVAN) is characterized by a collapsed glomerular capillary tuft with hyperplasia and hypertrophy of podocytes. Recently generated were conditional transgenic mice (podocin/Vpr) that express one of the HIV-1 accessory genes, vpr, selectively in podocytes using podocin promoter and Tet-on system. These transgenic mice developed renal injury similar to HIVAN when treated with doxycycline for 8 to 12 wk. This study demonstrated that nephron reduction by heminephrectomy markedly enhanced phenotypic changes of podocytes and led to severe FSGS within 4 wk. Nephrotic-range proteinuria was observed already at 2 wk, together with dedifferentiation and dysregulation of podocytes, indicated by decreased expression of nephrin, synaptopodin, and Wilms' tumor 1 protein and increased expression of Ki-67. The acceleration of phenotypic changes of podocytes, proteinuria, and subsequent glomerulosclerosis by heminephrectomy was almost completely inhibited by angiotensin II type 1 receptor (AT1R) blocker olmesartan. In contrast, the renoprotective effect of the calcium channel antagonist azelnidipine was minimal, although it lowered systemic BP to the same level as olmesartan, demonstrating that the inhibitory effect of AT1R blocker was independent of systemic BP. Olmesartan also reduced proteinuria and prevented glomerulosclerosis even by the delayed treatment, which was initiated after the podocyte injury appeared. These data suggest that nephron reduction exaggerates podocyte injury and subsequent glomerulosclerosis, possibly through glomerular hypertension, in the mouse model of HIVAN. AT1R blockade could be beneficial in the treatment of HIVAN by ameliorating podocyte injury by avoiding the vicious cycle of nephron reduction and glomerular hypertension.

Oxidative stress-dependent conversion of hydrogen sulfide to sulfite by activated neutrophils.

Sulfite, which is known as a major constituent of volcanic gas, is endogenously produced in mammals, and its concentration in serum is increased in patients with pneumonia. It has been reported that sulfite is produced by oxidation from hydrogen sulfide (H2S) as an intermediate in the mammalian body. The objective of this study was to investigate the ability of reactive oxygen species from neutrophils to produce sulfite from H2S. Sulfite production from activated neutrophils stimulated with N-formyl-methionyl-leucyl-phenylalanine gradually increased with an increased concentration of sodium hydrosulfide (NaHS) in the medium. The production of sulfite was markedly suppressed with an NADPH oxidase inhibitor, diphenyleneiodonium. When NaHS was added to the supernatant of activated neutrophils, a significant amount of sulfite was synthesized in the test tubes. Furthermore, when a medium containing NaHS was incubated with a water-soluble radical initiator, 2,2'-azobis-(amidinopropane) dihydrochloride, sulfite was formed in the solution and this increase was markedly suppressed by ascorbic acid. Finally, we determined serum concentrations of sulfite and H2S in an in vivo model of neutrophil activation induced by systemic injection of lipopolysaccharide (LPS) into rats. We found a significant increase in serum sulfite and H2S after LPS injection. Importantly, coadministration of ascorbic acid with LPS further increased serum H2S but suppressed sulfite levels. This finding implies that oxidative stress-dependent conversion of H2S to sulfite might occur in vivo. Thus, the oxidation of H2S is a novel sulfite production pathway in the inflammatory condition, and this chemical synthesis might be responsible for the upregulation of sulfite production in inflammatory conditions such as pneumonia.

Thiopurine methyltransferase genotype and phenotype status in Japanese patients with systemic lupus erythematosus.

We investigated the genotypic status of thiopurine methyltransferase (TPMT) polymorphism to evaluate the possible risk of the toxicity of azathioprine (AZA) in 68 patients with systemic lupus erythematosus (SLE). The allele frequency of TPMT mutation in the SLE group (2.9%) was higher than that in 174 Japanese healthy volunteers (1.1%), although it did not reach statistically significant difference (p=0.23). The mean value of TPMT activities in 51 subjects with TPMT*1/*1 was 40% higher than that of 4 subjects with TPMT*1/*3C in SLE group (18.1+/-6.1 nmol/h/ml packed red blood cells (pRBC) versus 13.2+/-3.2 nmol/h/ml pRBC; p=0.11). Two out of 4 SLE patients with TPMT*1/*3C had been treated with AZA, and one patient showed a leucopenia. The TPMT genotyping before AZA treatment is recommended for Japanese SLE patient group to avoid the AZA-induced adverse events, although detection of the patient with low TPMT activity by genotyping is still imperfect.

Comparison of the efficacy of an oral calcitriol pulse or intravenous 22-oxacalcitriol therapies in chronic hemodialysis patients.

BACKGROUND: 1,25-dihydroxy-22-ovavitamin D(3) (22-oxacalcitriol, OCT) was recently introduced commercially as an analogue of 1,25 (OH)(2) vitamin D(3), but one which has less pronounced calcemic activity. METHODS: To examine the efficacy and tolerability of OCT, 46 hemodialysis patients with secondary hyperparathyroidism were randomly assigned to receive either intravenous OCT or oral calcitriol pulse therapies. The patients were monitored for serum calcium, phosphate, intact parathyroid hormone (PTH), and bone alkaline phosphatase (BAP) for 24 weeks. The efficacy of intravenous OCT was also examined in 24 additional patients who were refractory to oral calcitriol pulse therapy. RESULTS: In the randomized trial, intact PTH levels were significantly suppressed within 4 weeks after the initiation of each therapy, and this effect was well maintained thereafter in both treatment groups. While intact PTH was significantly lower at 4 weeks in the calcitriol pulse group than in the OCT group (P = 0.02), no statistical differences were observed during later treatment periods. BAP was reduced equally by each treatment. At 4 weeks (P = 0.02) and thereafter (P = 0.06), serum calcium was higher among calcitriol-treated patients than among those who received OCT treatment. Eight of 24 patients who were refractory to oral calcitriol pulse therapy responded to intravenous OCT. The patients who responded tended to have lower serum intact PTH and phosphorus levels and smaller parathyroid glands at the start of OCT treatment than nonresponders. CONCLUSIONS: OCT is as effective as oral calcitriol pulse therapy in suppressing intact PTH and BAP in chronic hemodialysis patients. It was confirmed that OCT exhibits less calcemic activity than calcitriol. Moreover, under certain conditions, switching to OCT may help in the treatment of hyperparathyroidism, which is refractory to conventional oral calcitriol pulse therapy.

Secretion of parathyroid hormone oscillates depending on the change in serum ionized calcium during hemodialysis and may affect bone metabolism.

BACKGROUND: The current study was undertaken to clarify the dynamic response of parathyroid hormone (PTH) during hemodialysis and to determine whether or not such dynamic change of PTH affects bone turnover. METHODS: Serum ionized calcium (iCa) and intact PTH (iPTH) were measured in 66 dialysis patients before (basal) and after each hemodialysis. The changes of iCa (DeltaiCa) and iPTH (DeltaiPTH) were defined as [postdialysis iCa -basal iCa] mM, and [(postdialysis iPTH - basal iPTH)/basal iPTH] x 100%, respectively. We also investigated the data of the patients divided into four groups based on their basal iPTH levels; group 1 (iPTH < 60 pg/ml, n = 17), 2 (> or = 60 to < 150, n = 20), 3 (> or = 150 to < 300, n = 15), and 4 (> or = 300, n = 14). RESULTS: While iCa and iPTH changed variably during each hemodialysis procedure, there was a highly significant inverse correlation between DeltaiCa and DeltaiPTH (r = -0.761, p < 0.0001). Regression coefficients between DeltaiPTH and DeltaiCa were -519.1, -311.2, -268.1, and -194.6%/mM in groups 1-4, respectively. The difference in the regression coefficient was statistically significant between group 1 and 2 (F = 3.69, p < 0.05, ANCOVA), group 1 and 3 (F = 5.599, p < 0.05), and group 1 and 4 (F = 10.853, p < 0.005). This suggested that patients with higher basal iPTH responded poorly to modulate serum PTH levels by sensing the change of iCa. However, after an intensified oral calcitriol therapy to reduce iPTH, the PTH response in group 4 patients was restored to levels comparable with those observed in patients having lower basal iPTH. We also demonstrate that the DeltaiPTH of patients of group 1 but not of other groups was significantly correlated with serum markers for bone metabolism; osteocalcin (r = 0.535, p < 0.05) and collagen type I C-terminal telopeptide (r = -0.575, p < 0.05). CONCLUSIONS: Our findings suggest that secretion of PTH is dynamically regulated by DeltaiCa during hemodialysis and such oscillated PTH secretion may affect bone metabolism in a subset of dialysis patients.

Expression of interleukin-22 in rheumatoid arthritis: potential role as a proinflammatory cytokine.

OBJECTIVE: Interleukin-22 (IL-22) is a novel cytokine of the IL-10 family. Although its pathophysiologic function is largely unknown, induction of acute-phase responses by IL-22 has suggested proinflammatory properties. In this study, we sought to examine whether IL-22 plays a role in the pathogenesis of rheumatoid arthritis (RA). METHODS: Expression of IL-22 and IL-22 receptor 1 (IL-22R1) was examined by reverse transcription-polymerase chain reaction (RT-PCR), Western blot, and immunohistochemical analysis. The effects of recombinant IL-22 (rIL-22) on cultured synovial fibroblasts derived from RA patients (RASF), with regard to the proliferation of synovial fibroblasts and production of monocyte chemoattractant protein 1 (MCP-1), were examined by alamer blue assay and enzyme-linked immunosorbent assay, respectively. RESULTS: IL-22 messenger RNA was detected by RT-PCR in RA synovial tissues and mononuclear cells isolated from RA synovial fluid samples. High levels of IL-22 were expressed both in the lining and the sublining layers of RA synovial tissues. Staining for vimentin and CD68, as markers of synovial fibroblasts and macrophages, respectively, showed that the majority of IL-22-positive cells were synovial fibroblasts and macrophages. IL-22R1 was also expressed in both the lining and the sublining layers of RA synovial tissues. The majority of cells expressing IL-22R1 were positive for vimentin, but not for CD68. Expression of IL-22 and IL-22R1 in RASF was confirmed by RT-PCR and Western blot analysis. In vitro, rIL-22 significantly increased proliferation of RASF and production of MCP-1 by RASF above the value of medium controls. Moreover, MAPK activation was induced in RASF in response to IL-22 stimulation. CONCLUSION: These data suggest that IL-22, produced by synovial fibroblasts and macrophages, promotes inflammatory responses in RA synovial tissues by inducing the proliferation and chemokine production of synovial fibroblasts.

Water intoxication associated with moderate dose of cyclophosphamide pulse therapy in an elderly patient: a case report and literature review.

Intravenous high-dose cyclophosphamide infusion, usually performed to treat malignant neoplasms, is known to cause water intoxication. Intravenous cyclophosphamide pulse therapy (IVCY) is increasingly being employed for the treatment of rheumatic diseases as well. Recently, water intoxication has been reported to occur even after low-to-moderate doses of IVCY. In the present paper, we describe a case of polyarteritis nodosa in a patient in whom water intoxication developed after IVCY at a moderate dose. Hydration is usually performed to maintain sufficient urine flow to avoid cystitis. Based on our case and a review of the literature, it is recommended that hydration should be carefully performed during IVCY in order to avoid water intoxication, especially when treating elderly patients.

Mesangial cells stimulate differentiation of endothelial cells to form capillary-like networks in a three-dimensional culture system.

BACKGROUND: There are conflicting results regarding the role of periendothelial mural cells in angiogenesis. In the current study, we investigated the role of mesangial cells (MCs) in endothelial vascularization by using a three-dimensional co-culture system in basement-membrane reconstruct gel (Matrigel). METHODS: Human umbilical vein endothelial cells (ECs) and human MCs were used. In the contact co-culture system, ECs and MCs were mixed and then plated together onto Matrigel. In the non-contact co-culture system, MCs were cultured within an intercup chamber, which prevented direct physical contact with the ECs on the Matrigel but allowed both cell types to share culture medium. To visualize ECs and MCs, the cells were labelled with two different fluorescent dyes prior to the co-culture. A capillary-like network formation was observed under a fluorescent microscope and confocal microscope, and the length of the network formation was quantified by the image analyzer. RESULTS: ECs barely formed capillary-like networks when cultured alone in growth factor-free medium. However, ECs cultured with MCs in a contact condition remarkably formed capillary-like networks (9.10+/-0.96 vs 0.20+/-0.07 mm/mm2 at 6 h, contact vs ECs alone, P<0.001). Direct contact between ECs and MCs was clearly demonstrated by confocal microscopy. Differentiation into branching capillary-like structures was also observed in the non-contact co-culture system (3.02+/-1.21 mm/mm2 at 6 h, P<0.001 vs ECs alone), but less prominently than in the contact co-culture condition. Vascular endothelial growth factor (VEGF) was secreted from MCs, as determined by enzyme-linked immunosorbent assay and immunofluorescent study. Adding neutralizing antibodies against VEGF into the co-culture system partially inhibited capillary network formation. CONCLUSIONS: Our data indicate that MCs help ECs differentiate toward vascularization, in which the direct cell-cell contact between ECs and MCs plays an important role. VEGF is a mediator in this process.

Fluvastatin reduces renal fibroblast proliferation and production of type III collagen: therapeutic implications for tubulointerstitial fibrosis.

BACKGROUND: Accumulating evidence suggests that hydroxymethylglutaryl-CoA reductase inhibitors have many biological effects beyond reducing cholesterol synthesis. In a mouse model of renal interstitial fibrosis induced by unilateral ureteral obstruction, fluvastatin, one of the lipophilic hydroxymethylglutaryl-CoA reductase inhibitors, was shown to ameliorate fibrosis. METHODS: In the present study, we examined the direct effects of fluvastatin on proliferation, matrix and growth factor production by rat kidney fibroblasts (NRK-49F cells). RESULTS: Treatment with fluvastatin reduced proliferation of NRK-49F cells in a dose-dependent manner. The addition of mevalonate or geranylgeranyl pyrophosphate but not farnesyl pyrophosphate to the culture medium almost completely abolished the effect of fluvastatin. Moreover, fluvastatin treatment decreased the expression of activated Rho in NRK-49F cells suggesting that fluvastatin may decrease cell growth through blocking the activation of Rho. The majority of fluvastatin-treated cells were arrested at the G1 phase, associated with down-regulation of cyclin A and up-regulation of cyclin-dependent kinase inhibitor p27kip1, indicating that cell cycle modulation is an important mechanism. Fluvastatin significantly decreased messenger RNA expression of type III collagen and connective tissue growth factor. CONCLUSIONS: Taken together, it is suggested that fluvastatin may prevent tubulointerstitial fibrosis in a variety of progressive renal diseases by inhibiting proliferation of interstitial fibroblasts and their matrix synthesis.

Aplastic anemia associated with initiation of nizatidine therapy in a hemodialysis patient.

We report on a hemodialysis (HD) patient in whom fatal aplastic anemia developed after the administration of nizatidine, a histamine 2 (H2)-receptor antagonist. The patient was a 55-year old Japanese woman and had been on HD for 2 years due to endstage diabetic nephropathy. The patient had a hemorrhagic duodenal ulcer and had been treated with lansoprazole, a proton pump inhibitor, for 2 months. After improvement, lansoprozole was discontinued and she was subsequently treated with nizatidine. Twelve days after initiation of nizatidine treatment, the patient developed a high-grade fever with symptoms suggestive of upper respiratory infection. Hematological tests showed severe pancytopenia, and drug-induced aplastic anemia was diagnosed. Nizatidine was suggested as the causal drug. Despite intensive therapies, the patient died on the 23rd hospital day from generalized fungal infections. Although hematological adverse events have been reported in HD patients receiving H2-receptor antagonists, few studies of fatal aplastic anemia associated with these drugs have been reported. This case emphasized that careful observation is required after the initiation of H2-receptor antagonist treatment in HD patients.

Increased levels of serum sulfite in patients with acute pneumonia.

Sulfite, a common air pollutant, is toxic for humans, causing hypersensitivity or chronic airway diseases. We previously reported that sulfite is actively produced from neutrophils by stimulation with bacterial endotoxin, lipopolysaccharide (LPS). We also found that the serum sulfite concentration is increased in a rat model of sepsis induced by systemic injection of LPS. However, information on sulfite metabolism in human inflammatory conditions is limited. In the current study, the serum concentration of sulfite was determined in 25 patients with acute pneumonia. Serum sulfite concentration in pneumonia patients was significantly higher than that in control subjects (3.75 +/- 0.88 vs. 1.23 +/- 0.48 microM, respectively, P < 0.05). Among 20 patients, serum sulfite was serially determined before and after antibiotic therapy. The levels of serum sulfite were significantly reduced during the recovery phase compared with those during the acute phase (1.34 +/- 0.56 vs. 3.65 +/- 0.92 microM, respectively, P < 0.05). Moreover, neutrophils obtained from three patients during the acute phase of pneumonia spontaneously produced higher amounts of sulfite in vitro than those obtained after recovery. There was a close positive correlation (r = 0.71, P < 0.05) between serum sulfite and C-reactive protein (CRP) in patients with pneumonia. Taken together, the current findings suggest that serum sulfite increases during systemic inflammation in humans. Activated neutrophils might be responsible, at least in part, for the up-regulation of sulfite. Given various biological effects reported previously, sulfite may act as a mediator in inflammation.

Activin A induces cell proliferation of fibroblast-like synoviocytes in rheumatoid arthritis.

OBJECTIVE: To investigate the expression of activin A and its receptors in rheumatoid arthritis (RA) synovial tissues, and to determine the effect of activin A on cultured fibroblast-like synoviocytes (FLS). METHODS: The localization of activin A and activin type II receptor (ARII) in synovial tissues of RA patients was analyzed by immunohistochemistry. The expression of activin A and activin receptors in human cultured FLS was examined by reverse transcriptase-polymerase chain reaction and Western blotting. Enzyme-linked immunosorbent assay was used to measure activin A in culture supernatants. The cell growth of FLS was determined by (3)H-thymidine incorporation and MTT assay. RESULTS: Immunohistochemical analysis confirmed the up-regulation of activin A in rheumatoid synovium as compared with osteoarthritis or normal joint tissues. CD68+ macrophage-lineage cells and vimentin-positive FLS were identified as activin-producing cells in rheumatoid synovium. Both cell types also expressed ARII. The expression of activin A and ARII on cultured FLS was confirmed at the protein and messenger RNA levels. Interleukin-1 beta (IL-1 beta), tumor necrosis factor alpha, and transforming growth factor beta activated FLS to secrete activin A. Recombinant activin A accelerated the proliferation of FLS, while follistatin, an endogenous activin antagonist, partially inhibited FLS proliferation induced by IL-1 beta. CONCLUSION: These results suggest that activin A acts as a growth factor of FLS in RA.