Effect of a non-steroidal anti-inflammatory drug on tissue levels of immunoreactive prostaglandin E2, immunoreactive leukotriene, and pain after periodontal surgery

The aim of this study was to measure tissue levels of immunoreactive prostaglandin E2 (iPGE2), immunoreactive leukotriene B4 (iLTB4), and pain after periodontal surgery and to evaluate the effect of the non-steroidal anti-inflammatory drug (NSAID), ibuprofen, on these levels. Two contralateral quadrants in each of nine patients were selected to undergo separate surgical procedures, one with ibuprofen (800 mg 1 hour presurgery and 400 mg postsurgery) and one with a placebo. Intra-operatively, a custom-made microdialysis probe, with a 3,000 dalton molecular weight cut-off, was inserted beneath the soft tissue flap and a dialysate collected every 20 minutes for 4 hours after surgery. Pain perception was measured at the same time intervals using two pain scales. Dialysate samples were assayed using two enzyme immunoassays. Mean tissue levels of iPGE2 in the placebo group increased from 74 nM at 40 minutes to a peak of 261 nM at 200 minutes. Mean tissue levels of iLTB4 in the placebo group fluctuated between 0.2 and 0.6 nM. Pain levels in this group increased continuously with time, peaking at 4 hours. Mean tissue levels of iPGE2 in the ibuprofen group were significantly suppressed, exhibiting more than a 95% reduction. This was accompanied by a significant reduction in pain. Ibuprofen had no detectable effect on tissue levels of iLTB4. These data indicate that iPGE2 and iLTB4 are present at relatively high concentrations in the periodontal tissues after surgery. Since these concentrations exceed the Kd values for binding to their respective receptors, PGE2 and LTB4 may be associated with the development of postsurgical pain and inflammation. These data also indicate that ibuprofen can successfully inhibit iPGE2 production in the periodontal tissues and in this way may help reduce postoperative pain and inflammation.     

Potentiation of sufentanil by clonidine in PCEA with or without basal infusion

The purpose of the present study was to observe whether inflammatory mediators, such as: Prostaglandin E2 (PGE2), Bradykinin (BK), Histamine (HIS), Platelet active factor (PAF) and 5-hydroxytryptamine (5-HT), directly triggered the release of CGRP from perivascular nerves in isolated rat mesenteric arterial bed. The results showed that PGE2 (1-100 mumol/L) and BK (5-10 mumol/L) caused time- and concentration-dependent CGRP release, but HIS, PAF and 5-HT did not show significant effects. Our data indicate that PGE2 and BK are the major inflammatory mediators in triggering the release of CGRP from the perivascular CGRP-containing nerve.     

Airway obstruction caused by an oleothorax

PURPOSE: This article describes the possible role of various peptides in producing pain and inflammation in the temporomandibular joint (TMJ). MATERIAL AND METHODS: Current research findings on the spectrophotometric quantification of TMJ synovial fluid for neuropeptide Y (NPY), serotonin (5HT), and interleukin-1beta (IL-1beta) are presented. FINDINGS: NPY was found in high levels in the synovial fluid of arthritic TMJs with resting pain, and serotonin (5-HT) was found in patients with pain perceived on mandibular movement. These pain-related mediators were also associated with restricted mandibular mobility. Interleukin-1beta (IL-1beta) was found to be strongly associated with hyperalgesia over the TMJ as well as resting pain. Anterior open bite as a clinical sign of joint destruction was found to be associated with high levels of NPY and IL-1beta in the synovial fluid. IL-1beta was also related to the radiographic signs of joint destruction. CONCLUSIONS: Interaction between the peripheral nervous system (sensory and sympathetic nerves) and the immune system is probably of importance for the modulation of pain and inflammation in the TMJ, but this subject has to be investigated further with experimental clinical studies.     

Inhibition of cyclooxygenase-2 rapidly reverses inflammatory hyperalgesia and prostaglandin E2 production

PGs derived from cyclooxygenase-2 (COX-2), in particular PGE2, play important roles in the initiation of inflammation and pain. In the present study, we evaluated the role of COX-2-derived PGE2 in an animal model of established hyperalgesia. Inflammation and hyperalgesia were first induced by injection of carrageenan into rat footpads. Then we investigated the effects of subsequent therapeutic treatment with a selective COX inhibitor, with a nonsteroidal anti-inflammatory drug and with anti-PGE2 antibody. Test compounds were administered 1 to 3 hr after carrageenan challenge, and inhibition of pain (hyperalgesia, measured by withdrawal from a thermal stimulus), and changes in paw edema and PG levels were evaluated. The i.v. administration of a nonselective COX inhibitor, ketorolac, caused a rapid reduction in hyperalgesia in the inflamed footpad, returning it to near-normal values within 1 hr. Normal (control) paw response times were not affected. Therapeutic administration of ketorolac prevented most further swelling caused by carrageenan but did not reverse edema already present at the time of dosing. Administered p.o., a selective COX-2 inhibitor (SC-58635) was as efficacious as ketorolac in reducing inflammatory hyperalgesia. Footpad PG levels returned to base line or below within 5 min of dosing with ketorolac, which suggests rapid turnover of PG in the inflamed tissue. Therapeutic treatment with a monoclonal anti-PGE2 antibody also fully reversed the hyperalgesia response. These studies suggest that continuous production of PGE2 by the COX-2 enzyme is a critical element in sustaining the hyperalgesic response at sites of tissue inflammation.     

Responsiveness of slowly conducting articular afferents to bradykinin: effects of an experimental arthritis

Bradykinin (BK), an important inflammatory mediator and potent algogenic substance, is supposed to contribute to the generation of arthritic hyperalgesia and pain. The present study was undertaken to examine if an experimental kaolin/carrageenan arthritis sensitizes articular afferents to BK in the cat's knee joint using two different approaches. First, the proportion of afferent units activated by BK was assessed in fully inflamed joints and compared with corresponding data of normal knee joints. BK (injected i.a. as a bolus close to the joint) at the dose of 2.6 micrograms activated 60% of the units of groups II-IV in the inflamed state, compared to 71% in normal joints. The proportions of low- and high-threshold afferents activated by BK were similar, but more spontaneously active units than units without ongoing activity responded to BK both in inflamed and normal knee joints. Second, the responsiveness of individual afferent units to BK was examined during the development of inflammation. Units not activated by BK remained unresponsive after inflammation. From 11 units activated by BK, 3 units lost their responsiveness and in 4 other units the response to BK was reduced within 2-6 h after the onset of inflammation. Only in 4 units was the BK response increased in the inflamed joint. It is concluded that desensitizing rather than sensitizing processes are involved to change the response behavior of articular afferents to BK during acute experimental inflammation.     

The hypomobile temporomandibular joint

The hypomobile (restricted) temporomandibular joint (TMJ) is usually caused by a restricted joint capsule or by an anteriorly displaced disk. Here, painful unilateral hypomobility (19 mm jaw opening), with normal disk position, caused by voluntary immobilization after a dental procedure, was the presenting symptom. Management included inflammation control, TMJ manipulation (mobilization), and lateral pterygoid muscle relaxation. Inflammation and pain were alleviated by nonsteroidal anti-inflammatory drugs (NSAIDs) and local TMJ ice massage. TMJ mobilization was performed at every visit, to tear joint capsule adhesions and to realign collagen fibers. Exercise consisted mainly of resistive opening (the patient resists an upward force applied to the chin), with the jaw maintained at full opening. This produced lateral pterygoid muscle relaxation at full length, aiding in the restoration of a pain-free 44 mm opening.     

Arthritic temporomandibular joint: correlation of macromolecular contrast-enhanced MR imaging parameters and histopathologic findings

PURPOSE: To assess the utility of macromolecular contrast material-enhanced magnetic resonance (MR) imaging parameters for determining the histopathologic severity of temporomandibular joint (TMJ) arthritis. MATERIALS AND METHODS: Ovalbumin was used to induce arthritis in the TMJs of 10 previously sensitized adult white rabbits. Five rabbits composed the sham-treated control group. Dynamic spin-echo imaging was performed immediately before and for 30 minutes after injection of macromolecular contrast medium. Histologic specimens of TMJ were assessed quantitatively for arthritis. Changes in MR signal intensity were derived from the synovial and subsynovial tissues of the TMJ, and plasma volume (PV) and permeability surface area product (PS) were calculated. These MR parameters and the arthritic scores were compared between sham-treated and antigen-challenged TMJs. The relationships between MR parameters and histopathologic indexes were also determined. RESULTS: Arthritic TMJs showed marked enhancement of the synovial and subsynovial tissues over the imaging period. PS and all histopathologic indexes of arthritis were significantly greater (P < .005) in antigen-challenged than in sham-treated TMJs. PS demonstrated strong positive relationships with all histologic parameters of arthritis, indicating its utility for assessing the severity of joint inflammation. CONCLUSION: Macromolecular contrast-enhanced MR imaging enables quantification of PS and PV in inflamed joints. This technique may provide insights into the pathogenesis of joint inflammation and noninvasive monitoring of disease severity and treatment response in arthritis.     

Cytokine and nitric oxide production in the acute phase of bacterial cell wall-induced arthritis

We have investigated the temporal relationship among proinflammatory cytokine expression, nitric oxide (NO) production and joint inflammation in the acute phase of bacterial cell wall-derived peptidoglycan polysaccharide (PG/PS)-induced arthritis. Acute joint inflammation was induced in female LEW/N rats by a single intraperitoneal injection of PG/PS. Arthritis index and paw volume were quantified and joint histopathology was evaluated during acute joint inflammation (0-10 days). Tumor necrosis factor (TNF), interleukin-1 (IL-1) and interleukin-6 (IL-6) were determined by bioassay whereas nitric oxide (NO) was quantified by measuring serum nitrate/nitrite levels via the Griess procedure. We found that serum levels of TNF and serum IL-1 preceded the increase in IL-6 and NO production. Furthermore, the production of these proinflammatory cytokines and NO preceded bone erosion and osteoclast activity. Erosion of subchondral bone preceded pannus formation and cellular synovitis in the acute phase of PG/PS-induced arthritis. The temporal expression of TNF, IL-1, IL-6 and NO suggest a cascade of inflammatory mediators in which monocytes and macrophages respond to PG/PS with enhanced synthesis of TNF and IL-1, which may in turn promote the synthesis of IL-6 and NO. We postulate that one or more of these inflammatory events are responsible for initiating the subchondral bone erosion observed in acute joint inflammation.     

Involvement of endogenous kinins in the pathogenesis of peptidoglycan-induced arthritis in the Lewis rat

OBJECTIVE: To investigate the pathophysiologic roles of endogenous bradykinin (BK) and des-Arg9-BK on local and systemic inflammatory responses in a rat model of acute arthritis induced by peptidoglycan-polysaccharide (PG-APS). METHODS: Female Lewis rats were injected intraperitoneally with PG-APS. Selective antagonists of B1 (Lys-[Leu8]-des-Arg9-BK) and B2 (Hoe 140) receptors were infused at 500 microg/kg and 5 mg/kg per day for 6 days, starting 3 days before induction of inflammation, with subcutaneous micro-osmotic pumps. The local inflammatory response was assessed by paw edema, joint swelling, and tissue content of BK and des-Arg9-BK. These peptides were measured by highly sensitive and specific chemiluminescent enzyme immunoassays. Systemic inflammatory reaction was evaluated by the hepatic concentration of the type 2 acute-phase protein T-kininogen. RESULTS: PG-APS induced significant paw edema and joint swelling 24-72 hours after intraperitoneal injection. The maximal responses to PG-APS observed at 72 hours were significantly reduced (31-38%) by the combination of both B1 and B2 receptor antagonists at 5 mg/kg per day. PG-APS induced a significant increase of BK (up to 5.3-fold) and des-Arg9-BK (up to 4.1-fold) 72 hours after challenge. Liver T-kininogen content was increased by 5.3-, 7.7-, and 5.8-fold at 24, 48, and 72 hours, respectively, after PG-APS injection. At 24 hours, Hoe 140 and Lys-[Leu8]-des-Arg9-BK increased liver T-kininogen content by 43% and 45%, respectively, but they had no effect at 72 hours. CONCLUSION: The results indicate that endogenous kinins are involved in local and systemic acute inflammatory responses, through both B1 and B2 kinin receptors, in the model of PG-APS-induced arthritis.     

Mediators in polytrauma--pathophysiological significance and clinical relevance

Multiple trauma induces an inflammatory response syndrome of the whole body that is triggered by (a) hemorrhage inducing an ischemia/reperfusion (I/R) syndrome and (b) fractures or organ contusions inducing tissue-repair processes. I/R injury generates oxyradical/proteolytic metabolites and adhesion molecules, while tissue and endothelial injury directly stimulate complement, coagulation and kinin pathways. Membrane-derived phospholipase A2 and lipid mediators potentiate cellular interactions and increase microvascular permeability. The tissue-repair process mediates macrophage/monocyte and T-cell activation which releases pro- and anti-inflammatory cytokines. Mediator action follows a "three-level model", proposing that depending on the degree of traumatic injury cellular and humoral responses may spread from a cellular to an organ and then a systemic level. The systemic response can result in a severe immunological dys-homeostasis that potentially hazards the survival of the trauma patient by uncontrollable cellular dysfunction, appearing clinically as multiple organ-dysfunction syndrome. Blood-mediator concentrations often parallel the inflammatory process; initially, high levels of cytokines are followed by severe organ dysfunction. However, interpretation of these data remains difficult due to distinct beneficial or detrimental effects of mediators on the different levels of inflammation and missing prognostic threshold values, indicating a risk of adverse effects. Future studies must determine pro- and anti-inflammatory mediators directly, during the intensive care therapy, and evaluate their clinical relevance prospectively for the different levels of inflammation at local and systemic sites.     

Bradykinin stimulates type II alveolar cells to release neutrophil and monocyte chemotactic activity and inflammatory cytokines

In the present study, we evaluated the potential of bradykinin (BK) to induce the release of neutrophil and monocyte chemotactic activity (NCA and MCA) and cytokines from an alveolar type II epithelial cell line, A549 cells. BK stimulated A549 cells to release NCA and MCA in a dose- and time-dependent manner (P < 0.001). Checkerboard analysis revealed that both NCA and MCA involved chemotactic and chemokinetic activity. Molecular sieve column chromatography showed three molecular weight masses (near 19 kd, 8 kd, and 400 d) for NCA and several molecular weight peaks (near 66 kd, 25 kd, 19 kd, 16 kd, and 400 d) for MCA. The release of NCA and MCA was inhibited by cycloheximide and lipoxygenase inhibitors (P < 0.01). The NCA and MCA were inhibited by leukotriene B4 (LTB4) receptor antagonist (P < 0.01), and the concentration of LTB4 was high enough for NCA and MCA. Antibodies to interleukin (IL)-8 and granulocyte colony-stimulating factor (G-CSF) attenuated NCA (P < 0.01), and antibodies to monocyte chemotactic protein-1 (MCP-1), G-CSF, and transforming growth factor (TGF)-beta attenuated MCA (P < 0.01). The levels of IL-8, G-CSF, MCP-1, and TGF-beta increased time dependently (P < 0.01). BK also stimulated the release of ILeukin-6 from A549 cells (P < 0.001). The receptors responsible for the release of NCA, MCA, and individual chemokines involved both BKB1 and BKB2 receptors. These data suggest that BK may stimulate alveolar type II pneumocytes to release inflammatory cytokines, which then may modulate the lung inflammation.     

Long-lasting neuroprotective effect of postischemic hypothermia and treatment with an anti-inflammatory/antipyretic drug. Evidence for chronic encephalopathic processes following ischemia

BACKGROUND AND PURPOSE: It has been recognized that postischemic pharmacological interventions may delay the evolution of neuronal damage rather than provide long-lasting neuroprotection. Also, fever complicates recovery after stroke in humans. Here we report the effects of late postischemic treatment with hypothermia and an antipyretic/anti-inflammatory drug, dipyrone, on cell damage at 1 week and 2 months of survival. METHODS: Rats were subjected to 10 minutes of forebrain ischemia. Hypothermia (33 degrees C) was induced at 2 hours of recovery and maintained for 7 hours. Dipyrone (100 mg.kg-1IP) was given every 3 hours from 14 to 72 hours of recovery. Temperature was measured every 6 hours for 60 days. Neuronal damage was assessed at 7 days and 2 months of recovery. RESULTS: From 17 to 72 hours of recovery, a period of hyperthermia was observed, which dipyrone abolished but postischemic hypothermia treatment did not. Dipyrone treatment diminished neuronal damage by 43% at 7 days, and at 2 months of survival, a minor (16%) protection was seen. Postischemic hypothermia treatment alone delayed neuronal damage. In contrast, combined treatment of hypothermia followed by dipyrone markedly diminished neuronal damage by more than 50% at both 7 days and 2 months of recovery. CONCLUSIONS: Neuronal degeneration may be ongoing for months after a transient ischemic insult, and prolonged protective measures need to be instituted for long-lasting neuroprotective effects. Hyperthermia during recovery worsens ischemic damage, and processes associated with inflammation may contribute to the development of neuronal damage. An early and extended period of postischemic hypothermia provides a powerful and long-lasting protection if followed by treatment with anti-inflammatory/ antipyretic drug.     

Bradykinin stimulates phosphoinositide turnover and phospholipase C but not phospholipase D and NADPH oxidase in human neutrophils

In response to formyl-Met-Leu-Phe (fMLP), human neutrophils (PMN) generate superoxide anion (O2-) by the enzyme complex NADPH oxidase. The modulation of phosphoinositide (PPI) turnover and the activation of phospholipases C (PLC) and D (PLD) have been shown to be early steps in the oxidative response of fMLP-stimulated PMN. Although the physiological nonapeptide bradykinin (BK) is involved in inflammation, its participation in PMN activation has not been properly studied. In this work, activation of signal transduction pathways that mediate the oxidative response, and the modulation of the NADPH oxidase activity by BK, are analyzed. A direct comparison between the signal transduction pathway induced by BK and fMLP is also made. BK was not able to elicit O2- production by PMN. Nevertheless, several signal transduction pathways associated with PMN activation were triggered by BK. The nonapeptide induced the phosphorylation of prelabeled membrane PPI. This phenomenon was imitated by PMA and inhibited by H7 and staurosporine, thus suggesting the participation of protein kinase c (PKC). A loss of labeled [32P]PPI was triggered by fMLP. The fact that both PMA and fMLP stimulated O2- production but modulated PPI turnover in different ways, indicates that PPI labeling does not correlate with the oxidative response. Because PKC activation seemed to be a prerequisite for BK-induced modulation of PPI turnover, PLC activation could act as an intermediate step in this mechanism. Our results show that BK activated a PIP2-PLC measured as the release of [3H]IP3. On the contrary, a PC-PLD was highly stimulated by fMLP but not by BK. The fact that BK induced PLC activity but neither that of PLD nor NADPH oxidase, whereas fMLP triggered the activation of both phospholipases and evoked the PMN respiratory burst, suggests that diacylglycerol (DAG) from PIP2 as well as PA or PA-derived DAG, synergize to trigger the PMN oxidative response. Finally, BK inhibited O2- production by fMLP-activated PMN in a time-dependent manner. Since BK did not induce NO production by PMN, the inhibitory effect on the oxidative function was not due to ONOO- formation. These data show that BK plays an important role in inflammation by modulating the PMN function.     

Kinin receptors in the diabetic mouse

It has been proposed that kinins are important inflammatory mediators involved in the pathogenesis of several diseases. In the present study, we attempted to determine the effects of kinins in a type I diabetic mouse model, using in vitro assays. Injection of streptozotocin (STZ) to the C57BL/Ks mdb mice causes an insulitis (inflammation of Langerhans islets) that leads to the diabetic condition. Ten days following the STZ treatment, the mice showed increased glycemia. We examined the effect of kinins and other agents (substance P, neurokinin A, acetylcholine) on the stomach fundus and urinary bladder of control and diabetic mice. Our results show that the sensitivity of the stomach fundus to bradykinin (BK) and desArg9BK (DBK), but not to other contractile agents, was substantially increased in the tissues of diabetic mice. The maximal contractions induced by BK and DBK were increased 1.5- to 2-fold in the stomachs from diabetic mice compared with those from normal mice. BK induced similar maximal contractions of urinary bladder strips from normal or STZ-treated mice, while DBK did not show any effect on this preparation. Interestingly, the apparent affinities of all agonists are similar in the two groups, normal and diabetic. These results suggest that B1 and B2 receptors are overexpressed in the stomach fundus but not in the urinary bladder of diabetic mice.     

A highly repetitive sequence isolated from genomic DNA of the medaka (Oryzias latipes)

In order to investigate the relationship between various temporomandibular joint (TMJ) pain levels and the detection of high signal intensity (joint effusion) on T2 weighted magnetic resonance imaging (MRI), 19 consecutive patients who complained of unilateral painful TMJ hypomobility (closed locking) were involved in this study. All patients were clinically examined in a routine manner, and all patients rated their pain levels by a visual analogue scale and eight pain questionnaire prior MRI study. T1 and T2 weighted MRI was taken in sagittal section at unilateral affected joint side. The presence or absence of a high signal intensity spot within the TMJ compartment were judged by three examiners. The high signal intensity was detected in 10 joints, but not in 9 joints. In between these two groups, the pain ratio was calculated and compared. The data showed that there was no significant statistical correlation between pain levels and the presence of high signals. This study disclosed that the MRI detection of high signal intensity in the closed locking TMJ did not directly relate to the presence of TMJ pain nor the increased pain level. These indicate the need of further larger studies.     

The effect of intraperitoneal and intra-aortic chemotherapy for unresectable gastric cancer

Regional chemotherapy was given 16 unresectable gastric cancer patients. Two types of the chemotherapy, intraperitoneal (IP) and intraaortic (IA) administration, were carried out. The control group was comprised of 17 patients. The response of the chemotherapy for primary tumor was 36.4% in the IP group and 20% in the IA one. Among these patients, 2 of 11 in IP and 1 of 5 in IA were able to resect the primary tumor. The 50% survival time of IP, IA and control was 347, 227 and 78 days, respectively. One-year survival rates of IP, IA and control were 68%, 29% and 0%, respectively. IP showed a significantly longer survival rate than controls (p < 0.001). All but one patient was able to stay at home. Intraperitoneal chemotherapy showed both local and systemic effects in unresectable gastric cancer.     

Selective impairment of response to acetylcholine after ischemia/reperfusion in mice

BACKGROUND AND PURPOSE: We previously reported that the endothelium-dependent dilation of pial arterioles by either topical acetylcholine (ACh) or bradykinin (BK) was markedly inhibited after 10 minutes of near total ischemia after bilateral carotid occlusion. The present study tests the responses after 10 minutes of reperfusion and investigates the effect of either oxygen or oxygen radical scavengers on the results. METHODS: Mice were subjected to bilateral carotid ligation or sham ligation. Pial arteriolar diameters were monitored by an image-splitting technique at a craniotomy site. In separate studies, the responses to topically suffused ACh, BK, or sodium nitroprusside (SNP) were tested before ischemia. After 10 minutes of ischemia and 10 minutes of reperfusion, the response was assessed again. Sham-operated mice were observed in each study. Cerebral blood flow was continuously monitored with a laser-Doppler technique. Additional separate studies were conducted as follows: presence of superoxide dismutase plus catalase during ischemia and reperfusion, or increase in the inspired oxygen (arterial oxygen) and oxygen in suffusate. RESULTS: The response to ACh was significantly impaired after 10 minutes of reperfusion. The responses to BK and SNP were unaffected. Radical scavengers failed to influence the impaired response to ACh. Elevations of arterial and suffusate oxygen levels to over 300 mm Hg failed to prevent the impairment. CONCLUSIONS: After 10 minutes of reperfusion, a selective impairment of the response to ACh remains. The response to another endothelium-dependent dilator, BK, recovered, and the response to endothelium-independent SNP was unaffected. Because neither radical scavengers nor oxygen altered the outcome with respect to ACh, I suggest that neither radical generation nor hypoxia accounts for the selective impairment of dilation by ACh. Rather, I hypothesize that reduced shear during ischemia diminishes the ability of the endothelium to synthesize and/or release the endothelium-derived relaxing factor for ACh. I hypothesize further that this impaired release or synthesis persists throughout the 10-minute period of reperfusion.     

Making the most of aid

The synovial fluid (SF) of rheumatoid arthritis (RA) patients contains a mixture of inflammatory mediators. In order to determine whether certain cytokine patterns locally in the joint are specifically related to the chronic inflammation in RA, the concentrations of interleukin (IL)-1alpha, IL-1beta, IL-6, IL-10, transforming growth factor-beta (TGF-beta), tumour necrosis factor-alpha (TNF-alpha) and IgG2b-inducing factor (IgG2bIF) were measured in SF from 22 patients with RA and 22 patients with other types of arthritic lesions. High levels of IL-10, latent and active TGF-beta and the presence of IgG2bIF are significantly correlated with RA when corrected for age. As these factors have the capacity to promote antibody production, they might contribute to the maintenance of local antibody production in RA synovial tissues. All RA-SF samples contained detectable levels of IL-10 and all except one contained IL-1beta, while concentrations in several non-RA-SF samples were below detection limits. IL-6 and TGF-beta were present in all SF samples from both RA and non-RA patients. The presence of IgG2bIF was strongly correlated with high levels of IL-10 and IL-1beta in SF. However, no distinct cytokine profile specific for the chronic inflammation characteristic of RA was found.     

The mechanism of action of methotrexate

Because of methotrexate's well-documented efficacy in the treatment of rheumatoid arthritis, it is important that we understand the mechanism of action of this drug. There are two biochemical mechanisms by which methotrexate may modulate inflammation: (1) promotion of adenosine release and (2) inhibition of transmethylation reactions. Evidence is reviewed that favors the notion that the endogenous anti-inflammatory autocoid adenosine mediates the anti-inflammatory effects of methotrexate. This insight should aid in the design of new agents for the treatment of rheumatoid arthritis and other inflammatory diseases.