Pro-and Anti-inflammatory Cytokines in Rheumatoid Arthritis

Review Article

Pro- and Anti-inflammatory Cytokines in Rheumatoid Art h r i t i s

Pia Isomaki’ and Juha Punnonen’>*

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by the accumulation of inflammatory cells into the synovium and the destruction of joints. Cytokines are important regulators of the synovial inflammation. Some cytokines, such as tumour necrosis factor (TNF)-a and interleukin (11)-1 , function by promoting inflammatory responses and by inducing cartilage degradation. Other cytokines, such as 11-4, 11-1 0 and 11-13, function mainly as anti-inflammatory molecules. Although anti-inflammatory cytokines are present in rheumatoid joints, in progressive RA their levels obviously are too low to neutralize the deleterious effects of proinflammatory cytokines. Inhibiting the action of proinflammatory cytokines by using specific cytokine inhibitors or anti- inflammatory cytokines is the basis for new therapies currently tested in patients with RA. Promising results on the use of neutralizing anti-TNF-a monoclonal antibodies in the treatment of RA have been reported. The results from a trial using recombinant 11-10 in the treatment of patients with RA are available in the near future and will be important in determining the therapeutic potential of this cytokine.

Key words: cytokines; rheumatoid arthritis; synovium.

(Annals of Medicine 29: 499-507, 1997)

Introduction

Rheumatoid arthritis (RA) is a chronic autoimmune disease which is characterized by severe immune pathology. The primary target organ is the synovial lining of the joints and RA often leads to the erosion of articular cartilage and .bone. The accumulation of T lymphocytes, plasma cells and macrophages into the joints is a typical feature of RA. This migration into the joints is thought to be mediated by the increased expression of several adhesion molecules on synovial endothelial cells and by the action of chemotactic factors (1, 2).

The pathogenetic mechanisms driving the synovial inflammation in RA are incompletely understood. It is postulated that the activation of synovial T lymphocytes by antigen-presenting cells is the primary event in the

From the ‘Turku Immunology Centre and Department of Medical Microbiology, Turku University, Turku, Finland and ‘DNAX Research Institute, Palo Alto, CA, USA.

Address and reprint requests: Pia Isomaki, MD, Department of Medical Microbiology, Turku University, Kiinamyllynkatu 13, FIN-20520 Turku, Finland. Fax +358 2 233 0008, E-mail: [email protected].

initiation of synovial inflammation, which then leads to the activation of synovial macrophages by mechanisms so far unknown (Fig. 1) (1-3). However, there is some evidence that cell-cell contact may be important in the activation of macrophages, and possibly also other cell types, by synovial T lymphocytes (4, 5). At present, the (auto)antigen that drives T-lymphocyte responses in RA is not known, although collagen type II, other cartilage proteins and heat-shock proteins have been proposed as possible candidates (1). Of the CD4’ T lymphocytes, T-helper (Th)l cells which promote activation of inflammatory cells such as macrophages are enriched in rheumatoid synovium (6, 7) and are thought to promote synovial inflammation, whereas Th2 cells are considered anti-inflammatory, 6 lymphocytes are also activated in RA and plasma cells produce high levels of rheumatoid factors (8), but the role of 6 lymphocytes and rheumatoid factor in the pathogenesis of RA remains to be established.

In addition to lymphocytes, macrophages play an important role in synovial inflammation because they secrete high levels of proinflammatory cytokines (9). Some of these cytokines induce the expression of cartilage-degrading enzymes, including collagenase, and activate osteoclasts (Fig. 1). These events result ultima-

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500 lsomaki 0 Punnonen

tely in the degradation of articular cartilage and the underlying bone.

Cytokines and Arthritis

Cytokines are proteins with small molecular weight, which mainly function as soluble mediators. Based on their functional or structural similarities cytokines can be roughly divided into interleukins (IL), tumour necrosis factors (TNF), interferons (IFN), haemopoietic growth factors and chemokines. Cytokines regulate immune responses and also the growth and differentiation of haemopoietic, epithelial and mesenchymal cells. They generally have multiple activities on different cell types and the effects of two cytokines may be overlapping. Thus the cytokine network in an inflammatory response, such as that occurring in rheumatoid synovium, is extremely complex.

Cytokines are thought to be important as both disease-promoting (or proinflammatory) and disease- suppressing (or anti-inflammatory) mediators in rheumatoid joints (Table 1). Several cytokines are present in the joints of patients with RA. In particular, macrophage- derived cytokines have been detected at high levels and

many of these monokines function as potent proinflammatory molecules in the joints. Some of the macrophage-derived cytokines, such as IL-1 0, also possess anti-inflammatory activities. In contrast to monokines, T-lymphocyte-derived cytokines seem to be present at relatively low levels. However, as T lymphocytes are thought to secrete cytokines in a polarized manner towards the responding cells, the levels of T-lymphocyte cytokines detected in the joints may not represent the actual cytokine concentrations to which the responding cells are exposed.

In the following sections, we describe the putative pathogenetic significance of several pro- and anti- inflammatory cytokines in RA focusing on cytokines which have been studied extensively. We also reserve special attention to anti-inflammatory cytokines IL-4, IL-10 and 11-13, which have been the subjects of our own studies.

Proinflammatory cytokines in RA

Tumour Necrosis Factor-a

TNF-a is a macrophage-derived cytokine which has multiple proinflammatory effects. TNF-a is readily detect-

+ J n

Collagenase

Cartilage degradation Figure 1. A model of synovial inflammation in patients with rheumatoid arthritis. The activation of synovial T cells by antigen- presenting cells (APC) is likely to be important in the initiation of the inflammation. This leads to the activation of synovial macrophages by a mechanism (so far) unknown. Activated macrophages secrete proinflammatory cytokines, which induce cartilage degradation. Cellular interactions and possible stimulatory (-) and inhibitory (- - -) effects of cytokines on the synovial cells are presented. GM-CSF, granulocyle-macrophage colony-stimulating factor; IFN, interferon; IL, interleukin; MHC, major histocompatibility complex; TCR, T-cell receptor; TNF, tumour necrosis factor.


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Cytokines in Rheumatoid Arthritis 50 1

Table 1. Expression and the possible effects of cytokines in rheumatoid arthritis (RA).

Cytokine Expression in RA synovium

Possible effects in RA

GM-CSF IFN-7

IL-1

I L-4

IL-6

IL-10

IL-12 IL-13 IL-15

TGF-/I

TNF-K

+ + + + + +/-

+ + + + + + + +

+ + + +

Activation of macrophages Activation of macrophages Anti-inflammatory effects by unknown mechanism Cartilage degradation Systemic inflammation Downregulation of proinflammatory cytokines Induction of Th2 responses Activation of B lymphocytes Acute-phase response Downregulation of proinflammatory cytokines Inhibition of T-lymphocyte responses Induction of Thl responses and IFN-7 production Downregulation of proinflammatory cytokines Inflammatory cell recruitment Activation of T lymphocytes Induction of TNF-r production Inhibition of cartilage degradation Inflammatory cell recruitment Cartilage degradation Inflammatory cell recruitment Induction of proinflammatory cytokines

GM-CSF, granulocyte-macrophage colony-stimulating factor; IFN, interferon; IL, interleukin; TGF, transforming growth factor; Th, T helper; TNF, tumour necrosis factor. + +, + and +/- stand for different expression levels of cytokines in the synovium of patients with RA.

able in both synovial fluid (SF) and synovial tissue and is produced by cultured synovial cells in vitro (10-12). The fact that TNF-a is detected at the cartilage-pannus junction (1 3) suggests its involvement in cartilage degradation. The stimulus that drives TNF-a production in the inflamed synovium is not known, but IL-15 was shown recently to be a possible candidate (5).

In addition to TNF-a, soluble TNF-a receptors are present at increased levels in the joints of patients with RA (14). Soluble TNF-a receptors function as natural inhibitors of TNF-a, because they bind TNF-a and thereby block the association of TNF-a with its cell surface receptor. The amount of soluble TNF receptors produced in the synovial cell cultures was shown to be sufficient to block approximately half of TNF-r bioactivity

There is substantial evidence to support a pathogenetic role for TNF-a in synovial inflammation (16). TNF-c( stimulates collagenase and prostaglandin E production and induces cartilage and bone destruction in cell cultures (17, 18). In addition, it upregulates the expression of adhesion molecules on vascular endothelial cells and is chemotactic for monocytes and neutro- phils, leading to the accumulation of the inflammatory cells into the synovium.

Consistent with the in vitro studies, mice that overexpress TNF-a spontaneously develop destructive arthritis which is prevented by the administration of neutralizing anti-TNF-a monoclonal antibodies (mAb) (19). The fact that these mice develop arthritis, but apparently no other disease, indicates that the joint tissue is extremely sensitive to the proinflammatory effects of TNF-a. In addition, neutralizing anti-TNF-a mAb inhibit the development of synovitis in collagen- induced arthritis (20), a murine model of RA. Based on

(15).

these results and on the observation that TNF-a upregulates the production of other proinflammatory cytokines, including IL-1 , IL-6 and granulocyte-macrophage colony-stimulating factor (GM-CSF) by synovial cells (21-23), Feldmann et al. have proposed a model where TNF-r is at the apex of a proinflammatory cytokine network operating in rheumatoid synovium (24).

Interleukin- 1

IL-1 is a proinflammatory cytokine existing in two forms, IL-la and IL-lp, which bind to the same receptors and have similar activities. IL-1 is present in rheumatoid SF, although the levels of IL-1 are relatively low possibly due to the presence of inhibitors (25), and significant amounts of IL-1 are produced by cultured synovial cells in vitro (26). Similar to TNF-a, IL-1 can be detected at the cartilage-pannus junction (1 3).

A natural inhibitor of IL-1, IL-1 receptor antagonist (IL-lra) is also present in the joints of patients with RA (27, 28). IL-lra is homologous to IL-la and IL-lp and has high affinity for membrane IL-1 receptor. However, because IL-1 can activate the cells at very low receptor occupancy, a 10-100-fold excess of IL-lra is needed to block the effects of IL-1, whereas the ratio of IL-lra to IL-1 secretion by synovial cells was shown to vary between 1.2 and 3.6 (29).

IL-1 has several proinflammatory effects that may be important in the pathogenesis of RA. IL-1 induces prostaglandin E and collagenase production by synovial cells and promotes bone resorption in cell cultures (30, 31). IL-1 also upregulates the production of other proinflammatory cytokines, such as GM-CSF (32) and IL-6 (22), by synovial cells. In addition, the ability of IL-1 to induce fever and to promote the production of acute-


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phase proteins by liver cells may play a role in the systemic manifestations of RA.

Studies using animal models of arthritis support a pathogenetic role for IL-l in RA. Intra-articular injection of IL-1 into rabbit knee joints induces synovitis with an accumulation of inflammatory cells and cartilage destruction (33). In addition, systemic administration of IL-1 /I accelerates the development and progression of collagen-induced arthritis in mice (34). The central role of TNF-r in synovitis was questioned in a recent report on collagen-induced arthritis, which demonstrated that while anti-TNF-r treatment was efficient only shortly after disease onset, anti-IL-1 x / / j treatment ameliorated both early and late stages of the disease (35).

Other Proinflammatory Cytokines

The pathogenetic role of other proinflammatory cytokines in synovial inflammation is less well documented than that of TNF-a and IL-I. IL-6 is present at high levels in the SF from patients with RA and is also produced by the synovial cells in vitro (22, 25, 36). The serum levels of IL-6 in RA correlate with markers of disease activity (36). IL-6 increases B-cell proliferation and immuno- globulin (Ig) production, and may therefore stimulate rheumatoid factor secretion in the synovium. Similar to IL-1 , IL-6 enhances the secretion of acute-phase proteins by liver cells. IL-6 also induces osteoclast differentiation from haematopoietic precursors (37), and may therefore play a role in bone metabolism.

GM-CSF and M-CSF are also present in rheumatoid joints and are produced by cultured synovial macrophages (23, 32, 38). GM-CSF and M-CSF activate macrophages, for example to produce cytokines, and by inducing differentiation of myeloid cells they may increase the number of mature macrophages in the inflamed synovium (39). In addition, GM-CSF may contribute to the increased expression of major histocompatibility complex (MHC) class II molecules by synovial macrophages because the addition of anti- GM-CSF mAb to synovial tissue culture supernatants downregulates HLA-DR expression by monocytes (40).

IL-15, which is produced mainly by macrophages, was recently detected at high concentrations in rheumatoid SF and the chemotactic activity of SF towards T lymphocytes was in part attributable to the presence of IL-15 (41). IL-15 can induce proliferation of T lymphocytes and given the fact that IL-2 is present at relatively low levels in rheumatoid synovium IL-15 may be the major mitogenic factor in the joints of patients with RA. In addition, IL-15 was shown to induce TNF-a production by synovial macrophages via an effect on T lymphocytes and was also necessary to maintain the production of TNF-x in culture (5), suggesting that IL-15 may drive TNF-x production in rheumatoid joints.

Anti-inflammatory Cytokines in RA

Cytokines with anti-inflammatory properties have also been detected in the joints of patients with RA. These

include IL-10 derived mainly from macrophages and T-lymphocyte-derived cytokines IL-4 and IL-13.

Interleukin- 10

Human IL-10 consists of 160 amino acids and, in solution, it is present as a 39-kD homodimer. IL-10 is primarily produced by monocytes/macrophages, but CD4' and CD8' T lymphocytes and B lymphocytes also secrete IL-10 after activation (42-45). IL-10 expresses potent anti-inflammatory effects on both T-lymphocyte and monocyte functions. IL-10 directly inhibits the proliferation of T lymphocytes and it also has indirect inhibitory effects on T cells through downregulation of the antigen-presenting and accessory cell capacity of monocytes (46-48). In addition, IL-10 decreases the production of proinflammatory cytokines IL-1 x, IL-1 /I, IL-6, IL-8, IL-12, TNF-a, GM-CSF and G-CSF by human monocytes in vifro (44).

The importance of IL-10 as a negative regulator of inflammatory responses is illustrated in IL-1 0-deficient mice which are growth retarded and anaemic and develop a chronic inflammatory bowel disease resembl- ing Crohn's disease (49). It has also been shown that injection of recombinant IL-1 0 can protect mice from lethal endotoxaemia (50). In addition, IL-10 suppresses established collagen-induced arthritis in mice (51, 52), whereas neutralizing anti-IL-10 mAb increase the severity of arthritis (53).

Significant levels of IL-10 are present in the SF from patients with RA and IL-10 is spontaneously secreted by cultured synovial cells (54-56). Monocytes/macrophages are the main producers of IL-10 in patients with RA (55, 57). This endogenously produced IL-10 seems to function as an important anti-inflammatory molecule in rheumatoid joints, because the addition of neutralizing anti-IL-10 mAb to synovial cell cultures increases the production of proinflammatory cytokines, such as TNF-x, IL-lp, GM-CSF and IFN-7 (54, 56). Based on our results, in particular the production of TNF-r is dramatic- ally increased by anti-IL-10 mAb (56), suggesting that IL-10 is a major downregulator of TNF-cc production in rheumatoid joints.

In contrast to neutralizing anti-IL-10 mAb, the addition of recombinant exogenous IL-10 to synovial cell cultures downregulates the production of IL-lp and TNF-x and prevents cartilage degradation (54, 56, 58, 59), suggesting that IL-10 might be useful in the treatment of patients with RA (see below). In addition, exogenous IL-10 decreases the expression of HLA-DR molecules on SF macrophages and the proliferation of SF T lymphocytes (56), further emphasizing the anti-inflammatory potential of this cytokine in RA. These findings also support the notion that the amount of IL-10 that is produced by the synovial cells, although significant, is too low to neutralize the effects of proinflammatory cytokines in the joints of patients with RA.

Interleukin-4 and Interleukin- 13

IL-4 and IL-13 have a similarity of approximately 30% at the protein level and share many functions. IL-4 and


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Cytokines in Rheumatoid Arthritis 503

IL-13 are mainly derived from activated CD4' and CD8' T lymphocytes (60, 61). There are important differences in the production of these two cytokines. IL-4 is predominantly secreted by Th2 cells, whereas human IL-13 is produced by Tho, Thl, and Th2-type T-lymphocyte clones following activation (61). In addition, the accumulation of IL-13 mRNA in activated T lymphocytes occurs rapidly and is long-lasting when compared to the expression of IL-4 mRNA (61).

IL-4 and IL-13 have potent anti-inflammatory effects on monocytes, because they inhibit the production of several proinflammatory cytokines by monocytes in vitro, whereas the secretion of IL-lra is enhanced (62, 63). However, IL-4 and IL-13 enhance the expression of class II MHC molecules on monocytes (63), indicating that they are not only suppressors of monocyte functions. IL-4 and IL-13 also promote the proliferation and lg production by normal or immature B lymphocytes and induce B cells to switch to lgG4 and IgE production (64, 65). IL-4 and IL-13 have differential effects on T lymphocytes. In contrast to IL-4, which has well-described growth-promoting effects on T lymphocytes (66), IL-13 does not induce proliferation of peripheral blood T lymphocytes, suggesting that T lymphocytes lack functional IL-13 receptors. In addition, IL-13 does not promote the differentiation of Th2 cells

The studies on IL-4 production in rheumatoid synovium have yielded somewhat conflicting results. IL-4 mRNA has generally been detected in some, but not all, synovial samples studied (6, 68). IL-4 protein was originally reported to be absent or present in minimal amounts in SF samples from patients with RA (69), whereas in a recent study, IL-4 was detected in 6 of 9 synovial membrane samples using a newly developed immunohistochemical method (70). In our study IL-4 protein was present in the SF samples from 18 of 28 patients, but the levels of IL-4 were relatively low (71). In contrast, IL-13 was present consistently and at relatively high levels in the SF (71), suggesting that IL-13 might have a more important role than IL-4 in the regulation of synovial inflammatory responses in RA.

IL-4 has been shown to inhibit the production of proinflammatory cytokines by pieces of RA synovium (72), indicating its anti-inflammatory potential. It also decreases bone resorption in vitro (73) and systemically injected IL-4 suppresses the chronic destructive phase in streptococcal cell-wall-induced arthritis in rats (74). We have demonstrated that exogenous IL-13 significantly downregulates the production of TNF-r and IL-1 /l by SF mononuclear cells (71). IL-13 also inhibits bone resorption in vitro (75) and subcutaneous inoculation of vector cells engineered to secrete IL-13 attenuate collagen-induced arthritis in mice (76), further supporting the notion that IL-13 has anti-inflammatory potential in RA. The downregulation of cytokine production by IL-13 was comparable to that induced by IL-4, but less potent than that observed in response to IL-10 (71). Interestingly, the addition of IL-10 to IL-4, or IL-13-treated cultures further downregulated IL-1 /l production (71), suggesting that it would be beneficial to combine either IL-4 or IL-13 with IL-10 to inhibit

(67).

maximally the production of proinflammatory cytokines in arthritis.

Cytokines with Both Pro- and Anti- inflammatory Properties in RA

Transforming Growth Factor-/]

Transforming growth factor (TGF)-/I is a cytokine which has been implicated mainly as an anti-inflammatory mediator in the synovium. High levels of both latent and active TGF-P have been detected in SF and it is produced by cultured synovial cells in vitro (69, 77). In the synovial membranes, TGF-/j is mainly localized to the synovial lining, but it is also seen at sublining regions and at cartilage-pannus junction (77, 78).

TGF-/? induces collagen and inhibits collagenase mRNA expression by cultured synoviocytes (77) and thereby may counteract the cartilage-degrading activities of proinflammatory cytokines. TGF-/j also has potent immunoregulatory effects, such as inhibition of lymphocyte proliferation (79). Consistently, systemic TGF-/ll treatment suppresses the development of arthritis in susceptible rats (80). On the other hand, TGF-/j is chemotactic for monocytes and local injection of TGF-/I into rat joints was shown to induce inflammatory cell infiltration and synovial hyperplasia (81). In addition, locally administered anti-TGF-\j mAb decreased synovial inflammation in streptococcal cell wall-induced arthritis in rats (82). These results indicate differential effects for systemic and local treatments with TGF-/I. Therefore, in the absence of clinical data on the effects of TGF-/I in human RA it is difficult to conclude whether TGF-/? functions mainly as an anti-inflammatory or proinflammatory cytokine in arthritis.

Interferon-;, and Interleukin- 12

IFN-; is a T-lymphocyte-derived cytokine which is present in rheumatoid joints at mRNA level, but is detected at relatively low quantities at protein level (6, 83). IFN-7 is a potent macrophage-activating factor and can induce the expression of HLA-DR molecules on monocytes. However, the fact that the levels of IFN-y are not very high and the observation that the HLA-DR- inducing activity detected in SF cannot be neutralized by anti-IFN-; mAb (83) suggest that IFN-y may not be the major macrophage-activating factor in RA. IFN-y also directs the development of naive T cells into proinflammatory Thl phenotype. IFN--,. or anti-IFN-y treatments in collagen-induced arthritis have yielded somewhat conflicting results. In one report the severity of arthritis was significantly reduced when anti-IFN-y was administered together with type II collagen, or early after immunization, whereas later treatments with anti- IFN-; increased the severity of arthritis (84). This finding suggests that although IFN-;. is generally considered a proinflammatory cytokine, it may also have suppressing effects on arthritis. The mechanisms behind the anti- inflammatory effects of IFN-;. are not known.

IL-12 promotes IFN-y production and the generation of Thl cells and has been detected in rheumatoid joints


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(85). IL-12 induces severe arthritis in DBNl mice when administered together with type II collagen (86), indicating its pathogenetic potential. However, similar to IFN-y, IL-12 may have dual effects in arthritis, because high doses of IL-12 were recently shown to prevent the development of collagen-induced arthritis in mice (87).

Cytokines and Cytokine inhibitors in the Treatment of RA

The therapeutic agents currently used to treat patients with RA frequently have side-effects and their effectiveness may be marginal or transient. The possibilities to target the cytokine network in rheumatoid synovium are currently widely investigated. Recombinant forms of anti-inflammatory cytokines, such as IL-10, are studied in clinical trials in the treatment of RA, and efforts have been made to block the effects of harmful cytokines by using neutralizing anti-cytokine mAb, anti-cytokine receptor mAb, soluble cytokine receptors or naturally occuring cytokine inhibitors, such as 11-1 ra. However, several problems may be associated with these therapies. The half-life of recombinant cytokines in circulation is generally less than 30 minutes and therefore repeated injections are needed, which may increase the toxicity of the cytokine. Many of these compounds are immunogenic and some of the cytokine inhibitors may paradoxically have an agonistic rather than antagonistic effect in vivo. In addition, as most cytokines have several different activities, many of which are crucial for normal immune responses, these treatments might have severe side-effects, such as reduced resistance to infections or generation of autoimmune phenomena.

Cytokine Inhibitors

Few years ago Elliott et al. reported promising results on the use of TNF-a blockade in the treatment of patients with RA. Twenty patients with active RA received intravenous infusions of a total of 20 mg/kg body weight of chimeric (75% human lg) anti-TNF-a mAb (cA2). This treatment resulted in significant clinical and laboratory improvements lasting median for 12 weeks (88). The efficacy of this treatment was subse- quently verified in a randomized double-blind placebo- controlled trial (89). Significant declines in serum IL-1 p, IL-6, soluble CAM-1 and acute-phase protein levels were observed in patients treated with anti-TNF-x mAb (90). The treatment was well tolerated and only few adverse events were observed (89). However, the authors have reported that some patients treated with anti-TNF-a mAb develop anti-ds-DNA antibodies, suggesting that the development of a lupus-like syndrome may be a possibility (24). In addition, the clinical benefit and the decrease in proinflammatory cytokines after repeated infusions of anti-TNF-x mAb lasted for a shorter period of time than after the initial treatment. Patients treated with another anti-TNF-x mAb, mAb CDP571, also showed reduction in disease activity (91), but the effect was more modest than that observed

with cA2. Taken together, the results using anti-TNF-a treatment are promising and indicate for the first time that cytokine blockade may have a beneficial effect in RA. Future clinical trials using anti-TNF-a rnAb and soluble TNF-a receptors will demonstrate the effectiveness and safety of TNF-a blockade in the long-term management of RA and possibly also define the role of TNF-ct in RA pathogenesis.

The possibility of targeting IL-1 in the treatment of patient with RA has also been tested. In a randomized, double-blind study using IL-lra there was some suppression of disease activity in the treatment group receiving daily injections of IL-1 ra and the treatment was generally well tolerated (92). However, because there was no placebo arm in this study, the effectiveness of the therapy could not be definitely assessed and a placebo-controlled trial is in progress (92). In another study, patients with RA received daily subcutaneous injections of soluble 11-1 receptor type I . Only one of 19 patients treated with recombinant IL-1 receptor demonstrated clinical improvement (93). Therefore, the effectiveness of anti-IL-1 therapy has not been verified in patients with RA. It is possible, however, that the IL-1 blocking agents used in the studies have not been optimal and clinical trials to test different agents are on their way.

Anti-inf/ammatoiy Cytokines

The trials using cytokines in the treatment of patients with RA are not as far as those using cytokine inhibitors. Based on the beneficial results obtained using IFN-11 in some animal models of arthritis, IFN-y treatment has been tested in double-blind placebo-controlled studies in patients with RA. The results from these trials have been variable. In one study there were significantly more responders in the IFN-y treated group (94), whereas other trials did not show any significant differences between the groups treated with IFN-? and placebo (95, 96).

On the basis of in vitro data and studies on animal models, IL-10 is a possible candidate to be used in the treatment of RA. In vitro data suggests that IL-10 can significantly downregulate the production of proinflammatory cytokines by the synovial cells. On the other hand, IL-10 may also have minor proinflammatory effects because it promotes 6-cell activation and the production of rheumatoid factors in patients with RA (97). However, the phenotype of IL-1 0-deficient mice (49) and the effects of IL-10 treatment in animal models of inflammation (50-52) suggest that the anti-inflammatory actions of IL-10 dominate the proinflammatory ones. Recently, the administration of high doses of IL-10 was shown to be safe in a trial with 17 healthy volun- teers (98). In the same study, IL-10 injection suppressed mitogen-induced T-lymphocyte proliferation and significantly inhibited the production of IL-lp and TNF-a by endotoxin-stimulated whole blood (98). Taken together, the present results support the possibility that the use of IL-10 as a therapeutic agent in the treatment of patients with RA will be beneficial. Clinical trials using IL-10 in the treatment of patients with RA, as well as those with

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Crohn’s disease, have been started but as yet it is too early to draw conclusions on the effectiveness of IL-10.

IL-4 and IL-13 are other candidate cytokines to be used in the treatment of RA to downregulate the production of proinflammatory cytokines. Based on in vitro results, the anti-inflammatory effects of IL-4 and IL-13 on synovial macrophages are similar, but IL-13, unlike IL-4, does not induce synovial T-lymphocyte proliferation (71). On the other hand, IL-4, but not 11-13, can induce anti-inflammatory Th2 responses (67). These results suggest significant differences in the effects of IL-4 and IL-13 on the synovial inflammatory processes, and in vivo studies will determine whether there is a major difference in the anti-inflammatory potential of these two cytokines in RA. IL-4 has been previously administered to cancer patients at relatively high doses and numerous side-effects were observed. It is possible, however, that considerably lower levels of IL-4 would be sufficient to treat autoimmune diseases, such as RA. Circulating levels of IL-1 ra were shown to increase during IL-4 therapy (99), which is important when IL-4 is regarded as a therapeutic agent in RA. However, the safety and therapeutic efficacy of both IL-4 and IL-13 in humans still remains to be determined.

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Pro-and Anti-inflammatory Cytokines in Rheumatoid Arthritis