Synergistic activity of interleukin-4 and interleukin-10 in suppression of inflammation and joint destruction in rheumatoid arthritis.
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Animals↗
Biomedical subjects
J A van Roon
Publications and source records attributed to J A van Roon.
Interleukin 10 (IL-10), not IL-4 or interferon-gamma production, correlates with progression of joint destruction in rheumatoid arthritis.
OBJECTIVE: Both interleukin 4 (IL-4) and IL-10, separately and in combination, and under in vitro and in vivo conditions in animals, have been reported to inhibit characteristics of rheumatoid arthritis (RA) and experimentally induced arthritis. We investigated if IL-10 and IL-4 production, as well as interferon-gamma (IFN-gamma) production, opposing IL-4, were related to RA disease variables. A method was chosen to exclude the influence of age and disease duration. METHODS: We selected RA patients with mild and severe disease. Inclusion criteria were erythrocyte sedimentation rate (ESR) < or = 28 mm/h and > or = 50, C-reactive protein (CRP) < or = 20 and > or = 30, Thompson joint score < or = 60 and > or = 100 and radiographic joint damage score, Sharp score < or = 30 and > or = 40. Age and disease duration were restricted: 30 to 70 years and 5 to 15 years, respectively. Peripheral blood mononuclear cells were isolated and the ex vivo 48 h production of T cell IL-10, IL-4, and IFN-gamma (after CD3-CD28 stimulation) was assessed and was correlated to clinical variables. RESULTS: Only IL-10 production differed significantly between the 2 groups of RA patients, being highest in the "mild" group. Taking all patients together, a strong negative correlation was found between IL-10 production and radiographic joint damage (r = -0.53, p < 0.001) as well as progression of joint damage (r = -0.56, p < 0.0001). Similar negative correlations, although less powerful, were found between IL-10 production and ESR, CRP, and Thompson joint score. No correlation was found for IFN-gamma, IL-4, or the ratio of the 2 with disease activity variables or joint damage. CONCLUSION: The findings suggest that the high IL-10 production found in patients with RA may be protective, especially against progression of joint destruction in RA.
Adolescent↗
Apocynin, a plant-derived, cartilage-saving drug, might be useful in the treatment of rheumatoid arthritis.
OBJECTIVE: To investigate whether apocynin, 1-(4-hydroxy-3-methoxyphenyl)ethanone, is able to diminish inflammation-induced cartilage destruction in rheumatoid arthritis (RA), studied in a human in vitro model. METHODS: Apocynin was added to cultures of RA peripheral blood mononuclear cells (PBMNC). Cartilage-destructive activity was determined by addition of culture supernatant to tissue samples of human articular cartilage. In addition, the proliferation of PBMNC, their production of tumour necrosis factor alpha (TN-Falpha), interleukin (IL)-1 and IL-10, and T-cell production of interferon gamma (IFN-gamma) and IL-4, as measures for T1 and T2 cell activity, were determined. RESULTS: Apocynin was able to counteract RA PBMNC-induced inhibition of cartilage matrix proteoglycan synthesis, while no effect on inflammation-enhanced proteoglycan release was found. The effect was accompanied by a decrease in IL-1 and TNF-alpha production by the MNC. No effect on T-cell proliferation was found, but the production of IFN-gamma, IL-4 and T-cell-derived IL-10 was strongly diminished. Most important, apocynin did not show any direct adverse effects on chondrocyte metabolism; on the contrary, it diminished the release of proteoglycans from the cartilage matrix. CONCLUSION: Apocynin in vitro inhibits inflammation-mediated cartilage destruction without having adverse effects on cartilage. The latter may be an advantage of apocynin over many other non-steroidal anti-inflammatory drugs. Therefore, apocynin might have an added beneficial effect in protecting RA patients from joint destruction.
Acetophenones↗
The immune suppressive effect of dexamethasone in rheumatoid arthritis is accompanied by upregulation of interleukin 10 and by differential changes in interferon gamma and interleukin 4 production.
OBJECTIVES: The influence of dexamethasone on interleukin 10 (IL10) production and the type 1 (T1)/type 2 (T2) T cell balance found in rheumatoid arthritis (RA) was studied. METHODS: Peripheral blood mononuclear cells (PB MNC) were isolated from 14 RA patients both before and 7 and 42 days after high dose dexamethasone pulse therapy. The ex vivo production of IL10, interferon gamma (IFN gamma) (T1 cell), and IL4 (T2 cell) by PB MNCs was assessed, along with parameters of disease activity (erythrocyte sedimentation rate, C reactive protein, Visual Analogue Scale, Thompson joint score). In addition, the in vitro effect of dexamethasone (0.02, 0.2, and 2 microM) on PB MNC IL10, IFN gamma, and IL4 production was studied. RESULTS: Dexamethasone pulse therapy resulted in a rapid and sustained decrease in RA disease activity. IL10 production increased after dexamethasone treatment and this was sustained for at least six weeks. A transient strong decrease in IFN gamma was seen shortly after corticosteroid treatment, while IL4 only decreased slightly. This led to an increased IL-4/IFN gamma ratio. In vitro, IL10 production was not detectable, IFN gamma and IL4 decreased, but the effect was more pronounced for IFN gamma than for IL4, which again resulted in an increased IL4/IFN gamma ratio. CONCLUSION: Dexamethasone therapy in RA patients leads to a rapid, clinically beneficial effect. The upregulation of IL10 production may be involved in the prolonged clinical benefit. The strong immunosuppressive effect is most evident in the decrease in IFN gamma, and is therefore accompanied by a relative shift towards T2 cell activity. In vitro evaluation showed that this shift in T cell balance was a direct effect of dexamethasone and thus independent of the hypothalamic-pituitary-adrenal axis.
Adult↗
Mutual antagonism of rheumatoid arthritis and hay fever; a role for type 1/type 2 T cell balance.
OBJECTIVES: The balance between interferon gamma (IFN gamma) and interleukin 4 (IL4) producing T cells (T1 and T2 cells) seems to be of importance in many (auto)immune disorders. In general, T1 cell activity is important in cellular immunity whereas T2 cell activity plays a part in humoral responses. T1 cell activity predominates in joints of patients with rheumatoid arthritis (RA) whereas T2 cell activity is characteristic of atopic syndromes. This study investigated whether the prevalence of hay fever in RA is low and if severity of RA (T1 cell activity) can be influenced by the concomitant occurrence of a T2 cell mediated disease (hay fever). METHODS: The prevalence of hay fever was assessed in 643 consecutive (RA and non-RA) patients seen in our outpatient clinic and confirmed by skin test and specific IgE. Of this group the 12 RA patients with hay fever were compared with RA patients without hay fever (matched for age, sex, and disease duration). RESULTS: The prevalence of hay fever in RA patients is lower than in non-RA patients (4% versus 8%), and yields a relative risk for RA patients to develop hay fever of 0.48. RA patients with hay fever showed a lower disease activity (erythrocyte sedimentation rate, C reactive protein, Thompson joint score, and radiographic joint damage (Sharp) score) than RA patients without hay fever. The clinical data were related to peripheral blood T1/T2 cell balance: a lower IFN gamma/IL4 ratio was observed for RA patients with hay fever, indicating a comparatively increased T2 cell activity in RA patients with hay fever. CONCLUSION: These results argue in favour of the exploration of treatments aimed at regulation of a possible imbalance in T1/T2 cell activity in RA.
Adult↗
Stimulation of suppressive T cell responses by human but not bacterial 60-kD heat-shock protein in synovial fluid of patients with rheumatoid arthritis.
In several animal models of rheumatoid arthritis (RA), T cell responses to self 60-kD heat-shock protein 60 (hsp60) protect against the induction of arthritis. The nature of this suppressive T cell activity induced by self hsp60 is not clear. In the present study, T cell responses to human (self) hsp60 in RA in terms of type 1 (T1) and type 2 (T2) T cell activity were assessed. The results show that human and not bacterial hsp60-reactive synovial fluid (SF) T cells of patients with RA proliferate in the presence of the T2 cell growth factor IL-4. SF T cells stimulated with human hsp60 produced significantly lower amounts of IFN-gamma and higher amounts of IL-4 than SF T cells stimulated with bacterial hsp60 (P </= 0.002 and 0.05, respectively), and consequently a lower T1/T2 cell cytokine ratio was observed for human versus bacterial hsp60 (P </= 0.004). Additionally, human and not mycobacterial hsp60-specific T cell lines suppressed TNF-alpha production. Together, our results suggest that human hsp60, as overexpressed in inflamed synovium of patients with RA, can contribute to suppression of arthritis by the stimulation of regulatory suppressive T cell activity.
Adult↗
Decrease in peripheral type 1 over type 2 T cell cytokine production in patients with rheumatoid arthritis correlates with an increase in severity of disease.
OBJECTIVES: To compare peripheral type 1 (T1) and type 2 (T2) T cell activities in rheumatoid arthritis (RA) patients with that found for osteoarthritic (OA) patients and healthy controls and to correlate peripheral T1/T2 cell activity in RA with parameters of the disease. METHODS: Peripheral blood mononuclear cells were isolated from patients with RA (n = 66), OA (n = 19), and healthy controls (n = 15). Primary T cell activity in these mononuclear cells was enhanced by means of anti-CD3/anti-CD28, which mimicks stimulation of T cells by activation of the T cell receptor and a major co-stimulatory signal. Interferon gamma (IFN gamma) production and interleukin 4 (IL4) production in the three groups were quantified as measures of T1 and T2 cell activity, respectively, and compared. Serum tumour necrosis factor alpha (TNF alpha), erythrocyte sedimentation rate (ESR), C reactive protein (CRP), and joint destruction assessed radiographically of RA patients were determined as parameters of disease activity and correlated with T1/T2 cell activity. RESULTS: Peripheral T cells from RA patients produced significantly less IFN gamma and more IL4 than T cells from both age and sex matched OA patients and healthy controls. Moreover, in RA patients both a decrease in IFN gamma and an increase in IL4 production correlated with an increase in serum TNF alpha, ESR, CRP, and joint destruction. CONCLUSIONS: These results suggest a role for differential T cell activity in RA. In view of the intra-articular T1 cell predominance the results might be explained by selective T1 cell migration into the joint or peripheral suppression of T1 cell activity.
Aged↗
Prevention and reversal of cartilage degradation in rheumatoid arthritis by interleukin-10 and interleukin-4.
OBJECTIVE: Inflammation-induced articular cartilage degradation is a major problem in rheumatoid arthritis (RA). Type 1 T cell activity (characterized by interferon-gamma/interleukin-2 [IL-2] production), and consequently, the production of the proinflammatory cytokines IL-1 and tumor necrosis factor alpha (TNF alpha), have been reported to play a major role in cartilage damage. IL-10 and IL-4, both produced by type 2 T cells, are cytokines with the capacity to down-regulate proinflammatory responses. The present study was undertaken to investigate the way in which these cytokines affect activated mononuclear cells (MNC) of RA patients in relation to human articular cartilage degradation in vitro. METHODS: MNC from synovial fluid and peripheral blood of RA patients were stimulated with bacterial antigen and treated with IL-10 and/or IL-4. Bacterial antigen is known to activate type 1 T cells and to induce proinflammatory IL-1/TNF alpha-dependent cartilage damage. Cytokine production and effects of conditioned media, as well as effects of IL-10 and IL-4 on proteoglycan (PG) turnover (as a measure for cartilage damage), were determined. RESULTS: IL-10 and IL-4 inhibited proinflammatory cytokine production of stimulated RA MNC and completely reversed inhibition of cartilage PG synthesis induced by these stimulated RA MNC. IL-10 was more potent than IL-4 in this respect, and the combination of IL-10 and IL-4 had an additive effect. In addition, IL-10 directly stimulated cartilage PG synthesis. CONCLUSION: IL-10 reverses the cartilage degradation induced by antigen-stimulated MNC, and IL-4 has an additive effect on this process. Furthermore, IL-10 has a direct stimulatory effect on PG synthesis, and IL-4, as a growth factor for type 2 T cells, can reduce the ratio of type 1 to type 2 T cell activity. These results provide evidence in favor of the use of a combination of the two cytokines in the treatment of RA.
Adult↗
Proinflammatory cytokine production and cartilage damage due to rheumatoid synovial T helper-1 activation is inhibited by interleukin-4.
OBJECTIVES: To investigate the role of T helper-1 cell (Th1) activation in the induction of proinflammatory cytokine production and cartilage damage by rheumatoid arthritis (RA) synovial fluid mononuclear cells (SFMNC) and the subsequent possible beneficial role of the T helper-2 cell (Th2) cytokine interleukin-4 (IL-4) in the inhibition of this process. METHODS: SFMNC were stimulated with bacterial antigen (hsp60) to activate Th1 cells. Th1 and Th2 specific cytokine profiles (interferon gamma (IFN gamma) and IL-4) and proinflammatory cytokines interleukin-1 (IL-1) and tumour necrosis factor alpha (TNF alpha) in the conditioned media were analysed. In addition, the conditioned media were tested for their ability to induce cartilage damage. The same parameters were measured in the presence of IL-4. RESULTS: Stimulation of SFMNC with bacterial antigen resulted in an increase in IFN gamma, IL-1, and TNF alpha production which was accompanied by the induction of cartilage damage. Th1 activation could be inhibited by IL-4 as shown by a reduction of IFN gamma. This was accompanied by a decrease in IL-1 and TNF alpha production and inhibition of cartilage damage. CONCLUSIONS: Th1 activation is a possible mechanism by which inflammation in RA joints is enhanced. The Th2 cytokine IL-4 inhibits this Th1 activity and may diminish inflammation and induction of cartilage damage in RA joints.
Adult↗
The stimulation of mononuclear cells from patients with rheumatoid arthritis to degrade articular cartilage is not modulated by cartilage itself.
OBJECTIVE: To study the modulation of mononuclear cell (MNC) activity in patients with rheumatoid arthritis (RA) by constituents released from human articular cartilage, which may be present in vivo during early events of the disease, when articular cartilage is not only mildly damaged. METHODS: In an attempt to stimulate RA MNC, cells were co-cultured with healthy or mildly damaged articular cartilage tissue. In addition, because of the reported cross-reactivity between cartilage constituents and mycobacterial heat-shock protein (hsp60), RA MNC sensitized with hsp60 were also co-cultured with cartilage tissue. Activation of the RA MNC was assessed by analysing the production of catabolic factors involved in joint damage. For this purpose culture supernatants of the treated RA MNC, comprising the catabolic factors, were added to freshly isolated articular cartilage explants. As a read out for catabolic activity, proteoglycan (PG) turnover by the explants was determined. RESULTS: Spontaneous activity of untreated RA MNC caused inhibition of PG synthesis and increased PG release upon addition of their culture supernatants to the cartilage explants. This MNC activity was not enhanced by the constituents released from healthy or mildly damaged cartilage tissue, whereas sensitization of RA MNC with hsp60 resulted in a 40% enhanced inhibition of PG synthesis. However, even under these pre-activated conditions no reactivity towards the cartilage constituents could be observed. CONCLUSION: Cartilage constituents released from mildly damaged cartilage tissue, as may be present during the early events of RA. do not modulate the catabolic activity of RA MNC.
Adult↗