Inflammatory Response In Rheumatoid Arthritis Research Articles

Critical appraisal of tocilizumab in the treatment of moderate to severe rheumatoid arthritis

Recent advances in our understanding of the role of interleukin (IL)-6 in autoimmunity and in particular rheumatoid arthritis (RA) have brought about important changes in the way we think about autoimmune diseases. Encouraging data from several phase III clinical trials of tocilizumab, a humanized monoclonal antibody against IL-6R, have led to its approval in Europe for the treatment of moderate to severe RA. Data on clinical efficacy, patient-reported outcomes, safety, and cost-effectiveness with the use of tocilizumab in patients with RA will be summarized in this review, with particular emphasis on phase III clinical trials. Furthermore, adverse events associated with the use of tocilizumab will be reviewed. Future clinical trials will evaluate the role of tocilizumab in other autoimmune diseases. The goal of this review is to describe the current understanding of the role of IL-6 in mediating the inflammatory response in RA, as well as the role of tocilizumab in the treatment of RA and the evolving role of this agent in other autoimmune diseases.

A novel role for mitochondrial dysfunction in the inflammatory response of rheumatoid arthritis

The inflammation hypothesis of ageing suggests that molecular inflammation could be an underpinning of ageing and age-related diseases such as rheumatoid arthritis (RA). Besides, mitochondrial alterations may contribute to the...

Etanercept related pseudo-empyema in rheumatoid arthritis

Etanercept is a fusion protein that consists of extracellular ligand binding domain of the tumor necrosis factor alpha (TNF) receptor (p75) coupled with the Fc portion of human IgG. It binds TNF-α, thus blocking its interaction with TNF-α receptor. TNF-α is a proinflammatory cytokine that has a pivotal role in the inflammatory response in rheumatoid arthritis (RA). It also induces chemokine production and upregulates adhesion molecules. Indeed, etanercept is a mainstay therapy in RA [1]. Several pulmonary adverse reactions have been reported in patients treated with etanercept, the most important of which is tuberculosis. Other pulmonary complications include: granulomatous reaction, namely sarcoidosis (26 cases in the literature) [1–3], lung rheumatoid nodules [4], drug induced lupus related pleural effusion [5], and pulmonary lymphohistiocytic reactions [6]. In this report, we describe a case of severe RA pseudoempyematous pleural effusion that appeared with etanercept therapy and resolved promptly after its discontinuation.

Aktuelle Trends in Design und Entwicklung monoklonaler Antikörper gegen Entzündungsmediatoren zur Therapie der rheumatoiden Arthritis

As mediators of inflammation, cytokines contribute significantly to both the development and the extent of the inflammatory response in rheumatoid arthritis (RA). In addition, they regulate the differentiation of various cells involved in the pathogenesis of this disease. Tumour necrosis factor alpha (TNF alpha), interleukin (IL)-1 and IL-6 constitute prominent examples of such inflammatory cytokines and have been shown to play an important role in RA. As a consequence, the use of recombinant antibodies targeting these cytokines has revolutionized the treatment of RA. However, a considerable number of RA patients do not respond adequately to therapy with such biologics. Based on this notion, this article summarizes current trends in the design and development of monoclonal antibodies against inflammatory mediators. These include the identification of alterative target structures for anti-cytokine therapies, the specific modification of the antigen-binding CDR of therapeutic antibodies to reduce immunogenicity, alterations of the Fc part and the development of modified antibody fragments to improve the pharmacokinetics and to avoid non-specific immune reactions. Beyond that, efforts are undertaken to optimize the cost of these therapies.

Elevated expression of interleukin‐7 receptor in inflamed joints mediates interleukin‐7–induced immune activation in rheumatoid arthritis

To evaluate the expression and functional ability of the high-affinity interleukin-7 receptor (IL-7Ralpha) in patients with rheumatoid arthritis (RA). Expression of IL-7Ralpha and IL-7 was determined in synovial tissue from RA patients and was compared with that in synovial tissue from patients with undifferentiated arthritis (UA) and osteoarthritis (OA). IL-7Ralpha expression on CD4 T cells, CD19 B cells, and CD14 monocyte/macrophages from RA synovial tissue, synovial fluid, and peripheral blood was also assessed. The proliferative capacity of IL-7Ralpha(bright) and IL-7Ralpha(dim/-) T cells was measured. In addition, we examined IL-7R blockade with soluble human IL-7Ralpha (hIL-7Ralpha) in the prevention of immune activation of peripheral blood mononuclear cells. We found significantly higher IL-7Ralpha expression in RA and UA synovial tissue than in OA synovial tissue, and the level of IL-7Ralpha expression correlated significantly with the levels of CD3 and IL-7 expression. CD4 T cells from RA synovial fluid and synovial tissue strongly expressed IL-7Ralpha. A substantial percentage of B cells and macrophages from RA synovial fluid and synovial tissue also expressed IL-7Ralpha, although less prominently than T cells. We found that peripheral blood IL-7Ralpha(bright) T cells that did not express FoxP3 were highly proliferative as compared with IL-7Ralpha(dim/-) T cells that did express high levels of FoxP3. Soluble hIL-7Ralpha inhibited IL-7-induced proliferation and interferon-gamma production by mononuclear cells from RA patients. Our data suggest that enhanced expression of IL-7Ralpha and IL-7 in RA patients contributes significantly to the joint inflammation by activating T cells, B cells, and macrophages. The inhibition of IL-7R-mediated immune activation by soluble hIL-7Ralpha further indicates an important role of IL-7Ralpha in inflammatory responses in RA, suggesting IL-7Ralpha as a therapeutic target for immunotherapy in RA.

Expression and distribution of GABAergic system in rat knee joint synovial membrane.

The GABAergic system, found in the adult mammalian brain and composed of gamma-aminobutyric acid (GABA), GABA synthesizing enzyme glutamate decarboxylase (GAD) and GABA receptors, is also located in many peripheral nonneuronal tissues. Studies suggest that synovial membranes possess GABA, and that GABA participates in the control of the inflammatory response in rheumatoid arthritis (RA). However, no studies on the GABAergic system in synovial membranes have been done so far. Therefore, expression and distribution of the GABAergic system in the synovial membrane of the normal rat knee joint were investigated by reverse transcription-polymerase chain reaction (RT-PCR) analyses and immunohistochemistry. Results of RT-PCR analysis showed that mRNA encoding the GAD65 and GABAB receptor subunits necessary for the assembly of functional receptors, R1 and R2, are expressed in the synovial membrane. GAD and GABAB receptor subunits were localized in macrophage-like A cells of the synovial membrane. Macrophage-like A cells of the synovial membrane have a GABA production system and GABAB receptors, and GABA seems to play functional roles in the synovial membrane.

Bruton’s Tyrosine Kinase Is Involved in miR-346-Related Regulation of IL-18 Release by Lipopolysaccharide-Activated Rheumatoid Fibroblast-Like Synoviocytes

MicroRNAs (miRNAs) have emerged as key players in the regulation of expression of target mRNAs expression. They have been associated with diverse biological processes, and recent studies have demonstrated that miRNAs play a role in inflammatory responses. We reported previously that LPS-activated fibroblast-like synoviocytes (FLS) isolated from rheumatoid arthritis (RA) patients express IL-18 mRNA but they do not release IL-18. Based on the observation that this inhibition was due to a rapid degradation of IL-18 mRNA, our group has conducted a study to identify miRNAs that could play a role in the "antiinflammatory" response of LPS-activated RA FLS. LPS challenge modulated the expression of 63 miRNAs as assessed by microarray analysis. Fifteen miRNAs were up-regulated, including miR-346, for which overexpression upon LPS treatment was validated by quantitative RT-PCR. We then transfected FLS with an antisense oligonucleotide targeting miR-346 and found that, in these conditions, IL-18 release could be measured upon LPS activation of FLS. Moreover, we also demonstrated that miR-346 indirectly regulated IL-18 release by indirectly inhibiting LPS-induced Bruton's tyrosine kinase expression in LPS-activated RA FLS. These findings suggest that miRNAs function as regulators that help to fine-tune the inflammatory response in RA.

Bradykinin induces COX‐2 expression via MAPKs and NF‐κB in human synovial fibroblast of rheumatoid arthritis

Bradykinin (BK) is an important inflammatory mediator which has been shown to induce the expression of inflammatory proteins including COX‐2. However, the molecular mechanisms underlying BK‐induced COX‐2 expression in human fibroblast‐like synoviocytes (FLS) which contributes to inflammatory responses in rheumatoid arthritis (RA) were largely unknown. Here, our study aimed to investigate the mechanisms underlying the intracellular signalings involved in COX‐2 expression in BK‐induced inflammatory of human FLS. Western blotting and RT‐PCR analyses showed that BK induced COX‐2 protein and mRNA expression as well as phosphorylation of p42/p44 MAPK, p38 MAPK, and JNK which was attenuated by the inhibitors of MEK1/2 (U0126), p38 MAPK (SB202190), and JNK (SP600125). The involvement of MAPKs in these responses was further confirmed by that transfection with siRNA of p42, p38, or JNK2 attenuated BK‐induced COX‐2 expression. In addition, BK stimulated both IκB‐α degradation and NF‐κB translocation was attenuated by Bay11‐7082, U0126, SB202190, or SP600125. BK‐stimulated NF‐κB translocation into nucleus was further confirmed by immunofluorescence staining. These results suggest that in human FLS, BK‐induced COX‐2 expression was mediated through phosphorylation of MAPKs and NF‐κB pathways.

TNF‐α‐induced cyclooxygenase‐2 expression in human synoviocytes

COX‐2 is implicated in the pathogenesis of rheumatoid arthritis (RA) and has previously been shown to be induced by TNF‐α is implicated in the pathogenesis of rheumatoid arthritis (RA) and has previously been shown to be induced by TNF‐α. However, the molecular mechanisms underlying TNF‐α‐induced cyclooxygenase‐2 (COX‐2) expression in human synoviocytes (HS) which contributes to inflammatory responses in RA were largely unknown. Here, Western blotting and RT‐PCR analyses showed that TNF‐α induced COX‐2 protein and mRNA expression as well as phosphorylation of p42/p44 MAPK, p38 MAPK, and JNK which was attenuated by the inhibitors of MEK1/2 (U0126), p38 MAPK (SB202190), and JNK (SP600125), and transfection with siRNA of ERK1, p38, and JNK2, respectively. Furthermore, TNF‐α‐induced COX‐2 expression was inhibited by a selective NF‐¿B inhibitor (Bay11‐7082) and consistent with that TNF‐α stimulated both I¿B‐α degradation and NF‐¿B translocation into nucleus in these cells. NF‐¿B translocation was blocked by Bay11‐7082, but not by U0126, SB202190, and SP600125. Taken together, these results suggested that in HS, TNF‐α‐induced COX‐2 expression was independently mediated through phosphorylation of MAPKs and NF‐¿B pathways.

Association of the −1082 G/A promoter polymorphism of interleukin-10 gene with the autoantibodies production in patients with rheumatoid arthritis

Interleukin-10 (IL-10) is an immunoregulatory cytokine, usually considered to mediate the downregulation of the inflammatory response in rheumatoid arthritis (RA). Some effects of IL-10 are not anti-inflammatory; for example, the activation of B cells to promote autoantibody production. Allelic polymorphisms located in the promoter region of the IL-10 gene may contribute to the regulation of autoantibodies production. To examine the putative association between the -1082 G/A polymorphism in the promoter region of the IL-10 gene and the susceptibility to disease onset and severity of RA, a total of 144 patients with RA diagnosed according to the revised criteria of the American College of Rheumatology for RA were consecutively recruited into the study. Radiographic progression of RA was scored according to the Sharp/van der Heijde method. Serum levels of rheumatoid factors (RFs) were measured by enzyme-linked immunosorbent assay. Polymerase chain reaction amplification was used for the analysis of the promoter polymorphism of the IL-10 gene. We observed significant differences in genotype distribution of the -1082 G/A polymorphism between IgM RF, IgA RF, and IgG RF positive/negative subgroups of RA patients, with higher prevalence of the GG genotype within IgM RF (Pg = 0.006), IgA RF (Pg = 0.05), and IgG RF (Pg = 0.007) negative RA patients. Results obtained in this study provide the evidence of an association between the -1082 G/A polymorphism in the IL-10 gene promoter and the production of RFs in RA patients.

Effects of Antioxidant Supplements Intervention on the Level of Plasma Inflammatory Molecules and Disease Severity of Rheumatoid Arthritis Patients

Objective: Excess generation of reactive oxygen species in damaged joints accelerates inflammatory responses in RA (rheumatoid arthritis) patients. The complementary effects of dietary antioxidant supplementation on the blood level of inflammatory mediators and the severity of the disease in RA patients were evaluated.Study Design and Settings: The study was conducted as a randomized, placebo-controlled, double-blind, three-treatment cross-over design trial. The participants visited the hospital as outpatients.Subjects: Twenty patients meeting the 1987 criteria for the classification of rheumatoid arthritis completed the study.Interventions: The subjects were randomized in three groups to receive one of following supplementation; quercetin+vitamin C (166mg+133mg/capsule), α-lipoic acid (300mg/capsule) or placebo for 4 weeks (3 capsules/day). Each treatment period consisted of 4 weeks with 2 weeks of wash-out period before the subject starts next supplementation.Outcome Parameters: Serum levels of tumor necrosis factor-α(TNF-α), interleukin-1β(IL-1β), interleukin -6(IL-6), and C-reactive protein (CRP) were measured. The severity of disease was evaluated using Korean Health Assessment Questionnaire(KHAQ) and Visual Analogue Scale(VAS). Nutrient intake was measured at baseline and at the end of each intervention period.Results: The mean energy and nutrient intakes remained constant during study period. No significant differences were found in the serum concentrations of pro-inflammatory cytokines and CRP between treatments. The scores of disease severity measurements were not significantly different between treatments, although quercetin supplementation had a tendency to reduce VAS.Conclusions: Dietary supplementation of antioxidants at 900 mg/day for 4 weeks did not change the blood biomarkers of inflammation and disease severity of RA patients under conventional medical treatments. Further considerations for dose-response relationships, duration of supplementation, and susceptible biomarkers are required.

Bradykinin-induced IL-6 expression through bradykinin B2 receptor, phospholipase C, protein kinase Cδ and NF-κB pathway in human synovial fibroblasts

Bradykinin (BK) is an inflammatory mediator, and shows elevated levels in regions of severe injury and inflammatory diseases. It has been shown to induce interleukin-6 (IL-6) expression in inflammatory responses in rheumatoid arthritis. We investigated the signaling pathway involved in IL-6 production caused by BK in synovial fibroblasts. BK caused concentration- and time-dependent increases in IL-6 production. By using pharmacological inhibitors or genetic inhibition of the BK receptor, siRNA revealed that B2 but not B1 BK receptors are involved in BK-mediated up-regulation of IL-6. BK-mediated IL-6 production was attenuated by phospholipase C inhibitor (U73122), protein kinase Cδ inhibitor (rottlerin), NF-κB inhibitor (PDTC), IκB protease inhibitor (TPCK) and NF-κB inhibitor peptide. Stimulation of synovial fibroblasts with BK activated IκB kinase α/β (IKK α/β), IκBα phosphorylation, IκBα degradation, p65 phosphorylation at Ser 276, p65 and p50 translocation from the cytosol to the nucleus and κB-luciferase activity. BK mediated an increase of IKK α/β and IκBα phosphorylation, κB-luciferase activity and p65 and p50 binding to the NF-κB element was inhibited by B2 BK receptor antagonist (HOE140), U73122 and rottlerin. Our results suggest that BK increased IL-6 production in synovial fibroblasts via the B2 BK receptor/PI-PLC/PKCδ/and NF-κB signaling pathway.

Redox signalling and the inflammatory response in rheumatoid arthritis

Reactive oxygen species (ROS) are produced mainly during oxidative phosphorylation and by activated phagocytic cells during oxidative burst. The excessive production of ROS can damage lipids, protein, membrane and nucleic acids. They also serve as important intracellular signalling that enhances the inflammatory response. Many studies have demonstrated a role of ROS in the pathogenesis of inflammatory chronic arthropathies, such as rheumatoid arthritis. It is known that ROS can function as a second messenger to activate nuclear factor kappa-B, which orchestrates the expression of a spectrum of genes involved in the inflammatory response. Therefore, an understanding of the complex interactions between these pathways might be useful for the development of novel therapeutic strategies for rheumatoid arthritis.

Role of tumor necrosis factor‐alpha in rheumatoid arthritis: a review

AbstractTumor necrosis factor‐alpha (TNF‐α) is a proinflammatory cytokine that plays a pivotal role in regulating the inflammatory response in rheumatoid arthritis (RA). Although it is controversial whether TNF‐α genes are associated with RA susceptibility, they are well known to mediate RA pathogenesis. We review in depth the history, formation and biological action, TNF receptor, role in mediating pathogenesis in RA and mode of action, of anti‐TNF‐α drugs.

Interleukin (IL)-23 p19 expression induced by IL-1 in human fibroblast-like synoviocytes with rheumatoid arthritis via active nuclear factor- B and AP-1 dependent pathway

To explore the source of the p19 subunit of interleukin-23 (IL-23) in joints with rheumatoid arthritis (RA), the effects of IL-1beta and tumour necrosis factor (TNF)-alpha on IL-23 gene expression in RA fibroblast-like synoviocytes and the effect of IL-23 on proinflammatory cytokines. Expression of IL-23 p19 in joints was examined by immunohistochemical analysis of patients with RA and osteoarthritis (OA). The effects of IL-1beta and TNF-alpha on the expression, of IL-23 p19 and IL-12 p35 subunits in human fibroblast-like synoviocytes from RA patients (HFLS-RA) were determined by reverse transcriptase polymerase chain reaction (RT-PCR), quantitative PCR and western blotting assay. Blockade of nuclear factor kappaB (NF-kappaB) or AP-1 activation was used to verify the involvement of intracellular signal pathways of the induction of p19. IL-23-induced IL-8 and IL-6 productions were determined in HFLS-RA by RT-PCR and enzyme-linked immunosorbent assay. IL-23 p19 was expressed in the synovium from RA, but not from OA patients. Similar to the protein expression, IL-23 p19 mRNA could be detected by RT-PCR in four of five RA synovial fluid mononuclear cells (SFMC). IL-1beta and TNF-alpha could induce RA fibroblast-like synoviocytes to produce the IL-23 p19 subunit. The effects of IL-1beta were much stronger than TNF-alpha. These responses were observed in both a dose-responsive and time-dependent manner. IL-1beta produced weakly enhanced gene expression of the p35 subunits of IL-12. IL-1beta also promotes the p35 expression, a subunit of IL-12, but weakly. In addition, the NF-kappaB and the AP-1 inhibitors down-regulated the expression of IL-23 p19 mRNA induced by IL-1beta. IL-23 receptor (IL-23R) was of constitutive expression in HFLS-RA. Moreover, IL-23 up-regulated the IL-8 and IL-6 mRNA and protein levels in a dose-dependent manner in HFLS-RA. Our results demonstrate that IL-23, produced by mononuclear cells in synovial fluid with RA and HFLS-RA, promotes inflammatory responses in RA by inducing IL-8 and IL-6 production from HFLS. IL-1beta regulates IL-23 p19 expression via NF-kappaB and AP-1 pathways. This report also demonstrates that IL-23 could promote inflammatory responses in HFLS-RA by stimulating IL-8 and IL-6 production.

Novel action of n‐3 polyunsaturated fatty acids: Inhibition of arachidonic acid–induced increase in tumor necrosis factor receptor expression on neutrophils and a role for proteases

Neutrophils and tumor necrosis factor (TNF) play important roles in the pathogenesis of rheumatoid arthritis (RA). Modulation of TNF receptors (TNFRs) may contribute to the regulation of tissue damage, and n-6 polyunsaturated fatty acids (PUFAs) such as arachidonic acid (AA) can increase the expression of TNFRI and TNFRII on neutrophils. Because the n-3 PUFAs are antiinflammatory in RA, we examined whether, as a novel mechanism of action, n-3 PUFAs can antagonize the AA-induced increase in TNFR expression. Human neutrophils were treated with PUFAs and examined for changes in surface expression of TNFRs by flow cytometry. Translocation of protein kinase C (PKC) and activation of ERK-1/2 MAPK were determined by Western blotting. Intracellular calcium mobilization was measured in Fura 2-loaded cells by luminescence spectrometry. Pretreatment of neutrophils with nanomolar levels of n-3 PUFAs, eicosapentaenoic acid, or docosahexaenoic acid led to a marked inhibition of the AA-induced up-regulation of TNFRs I and II. Such pretreatment, however, did not prevent AA from stimulating the activities of PKC and ERK-1/2, which is required for the actions of AA or its ability to mobilize Ca(2+). Nevertheless, treatment with n-3 PUFAs caused the stimulation of serine proteases that could cleave the TNFRs. These findings suggest a mechanism by which the n-3 PUFAs inhibit the inflammatory response in RA, by regulating the ability of AA to increase TNFR expression. These results help fill the gaps in our knowledge regarding the mechanisms of action of n-3 PUFAs, thus allowing us to make specific recommendations for the use of n-3 PUFAs in the regulation of inflammatory diseases.

Identification of citrullinated α-enolase as a candidate autoantigen in rheumatoid arthritis

Antibodies against citrullinated proteins are highly specific for rheumatoid arthritis (RA), but little is understood about their citrullinated target antigens. We have detected a candidate citrullinated protein by immunoblotting lysates of monocytic and granulocytic HL-60 cells treated with peptidylarginine deiminase. In an initial screen of serum samples from four patients with RA and one control, a protein of molecular mass 47 kDa from monocytic HL-60s reacted with sera from the patients, but not with the serum from the control. Only the citrullinated form of the protein was recognised. The antigen was identified by tandem mass spectrometry as α-enolase, and the positions of nine citrulline residues in the sequence were determined. Serum samples from 52 patients with RA and 40 healthy controls were tested for presence of antibodies against citrullinated and non-citrullinated α-enolase by immunoblotting of the purified antigens. Twenty-four sera from patients with RA (46%) reacted with citrullinated α-enolase, of which seven (13%) also recognised the non-citrullinated protein. Six samples from the controls (15%) reacted with both forms. α-Enolase was detected in the RA joint, where it co-localised with citrullinated proteins. The presence of antibody together with expression of antigen within the joint implicates citrullinated α-enolase as a candidate autoantigen that could drive the chronic inflammatory response in RA.

Defining a role for fibroblasts in the persistence of chronic inflammatory joint disease

The most surprising feature of the inflammatory response in rheumatoid arthritis is not that it occurs but that it does not resolve. The persistence of the chronic inflammatory response in...

Expression of mitogen-activated protein kinase phosphatase 1, a negative regulator of the mitogen-activated protein kinases, in rheumatoid arthritis: up-regulation by interleukin-1beta and glucocorticoids.

Mitogen-activated protein kinases (MAPKs) are activated by proinflammatory stimuli. MAPK phosphatases (MKPs), in particular MKP-1, have been identified as endogenous negative regulators of MAPK activation. Since MAPKs are known to be important in rheumatoid arthritis (RA) synoviocyte activation, this study assessed the expression, regulation, and function of MKP-1 in RA. MKP-1 expression was measured by Western blotting (WB) and real-time polymerase chain reaction (PCR). RA fibroblast-like synoviocytes (FLS) were treated with interleukin-1beta (IL-1beta), tumor necrosis factor alpha, fetal calf serum, and dexamethasone. Expression of MAPKs in RA FLS was analyzed by WB using phosphospecific antibodies, while IL-6 expression was assessed by real-time PCR. MKP-1 protein and messenger RNA were detected in cultured RA FLS. IL-1beta rapidly up-regulated MKP-1, coinciding with reciprocal down-regulation of ERK, JNK, and p38 MAPK phosphorylation. Dexamethasone rapidly and sustainably up-regulated MKP-1, and this also coincided with down-regulation of ERK, JNK, and p38 MAPK phosphorylation. In addition, dexamethasone augmented IL-1beta-induced up-regulation of MKP-1, and this was associated with inhibition of ERK, JNK, and p38 MAPK phosphorylation and IL-6 expression. Dexamethasone had no effect on the phosphorylation of upstream kinases such as MEKK-3/6. In the presence of glucocorticoid (GC) receptor antagonist RU 486, the dexamethasone-mediated up-regulation of MKP-1 was impaired. Moreover, inhibition of MKP-1 expression impaired dexamethasone-mediated inhibition of MAPK phosphorylation. This study demonstrates the expression of MKP-1 in RA FLS. Cytokine and GC regulation of MKP-1 may be important in determining the magnitude of the inflammatory response in RA that is mediated via MAPKs. The effects of GCs in RA may be mediated, in part, via GC receptor-dependent up-regulation of MKP-1.

Effect of phospholipase A2 inhibitory peptide on inflammatory arthritis in a TNF transgenic mouse model: a time-course ultrastructural study

We evaluated the therapeutic effect of secretory phospholipase A2 (sPLA2)-inhibitory peptide at a cellular level on joint erosion, cartilage destruction, and synovitis in the human tumor necrosis factor (TNF) transgenic mouse model of arthritis. Tg197 mice (N = 18) or wild-type (N = 10) mice at 4 weeks of age were given intraperitoneal doses (7.5 mg/kg) of a selective sPLA2 inhibitory peptide, P-NT.II, or a scrambled P-NT.II (negative control), three times a week for 4 weeks. Untreated Tg197 mice (N = 10) were included as controls. Pathogenesis was monitored weekly for 4 weeks by use of an arthritis score and histologic examinations. Histopathologic analysis revealed a significant reduction after P-NT.II treatment in synovitis, bone erosion, and cartilage destruction in particular. Conspicuous ultrastructural alterations seen in articular chondrocytes (vacuolated cytoplasm and loss of nuclei) and synoviocytes (disintegrating nuclei and vacuoles, synovial adhesions) of untreated or scrambled-P-NT.II-treated Tg197 mice were absent in the P-NT.II-treated Tg197 group. Histologic scoring and ultrastructural evidence suggest that the chondrocyte appears to be the target cell mainly protected by the peptide during arthritis progression in the TNF transgenic mouse model. This is the first time ultrastructural evaluation of this model has been presented. High levels of circulating sPLA2 detected in untreated Tg197 mice at age 8 weeks of age were reduced to basal levels by the peptide treatment. Attenuation of lipopolysaccharide- and TNF-induced release of prostaglandin E2 from cultured macrophage cells by P-NT.II suggests that the peptide may influence the prostaglandin-mediated inflammatory response in rheumatoid arthritis by limiting the bioavailability of arachidonic acid through sPLA2 inhibition.