Unmasking the anti-inflammatory cytokine response in rheumatoid synovitis
R. Gerli,
C. Lunardi1 and
C. Pitzalis2
Department of Clinical and Experimental Medicine, Section of Internal Medicine and Oncological Sciences, Center for the Study of Rheumatic Diseases, University of Perugia, Perugia,
1 Department of Clinical and Experimental Medicine, Section of Internal Medicine, University of Verona, Verona, Italy and
2 Department of Rheumatology, Division of Medicine, Guy's and St Thomas' School of Medicine (GKT), Guy's Campus, London, UK
The contribution of T lymphocytes to the pathogenesis of rheumatoid arthritis (RA) remains a matter of intense debate. Few people, however, would question the central role of T cells in initiating and modulating RA immune pathogenesis via the recognition of some unknown (exogenous/auto-)antigens in the joint and the production of various cytokines [13]. In this regard, there is general agreement that RA synovitis is a Th1-dominated disease [4]. Th1 cells, indeed, are prominent among the T cells isolated from the synovium of patients with RA [57]. In addition, T-cell clones from the rheumatoid joint produce predominantly proinflammatory cytokines, such as interleukin (IL)-2, interferon (IFN)-
and IL-12 [8, 9]. Selective enrichment of Th1 cells in the RA synovium is also suggested by single-cell analysis of synovial CD4+ T cells that demonstrates greater production of the Th1 cytokine IFN-
compared with paired peripheral blood CD4+ T cells from the same patient [10]. These Th1 cytokines would, in turn, activate macrophage/synoviocytes to produce joint-destructive cytokines and other inflammatory mediators, such as tumour necrosis factor (TNF)-
, IL-1 and metalloproteases [1, 3].
Against this proinflammatory background, there is evidence to indicate that a number of anti-inflammatory homeostatic mechanisms are set in motion in the joint in an attempt to modulate the inflammatory/immune response [4]. Among these are mechanisms involving antagonists of inflammatory mediators, including the IL-1 receptor antagonist and the soluble TNF receptor, as well as cytokines with anti-inflammatory properties, such as transforming growth factor ß, IL-13, IL-10 and IL-4 [1118]. These last two cytokines, in particular, have been investigated extensively in recent years for their well-documented protective effect against inflammation and joint destruction in various animal models of arthritis and other Th1-type disorders [4, 19]. Recently, it has been highlighted that the down-modulatory activity would be essentially exerted through a synergistic effect of IL-4 and IL-10 that, in turn, would neutralize the potentially dangerous effects of the individual cytokines [20].
Although there is universal agreement on the fact that low levels of anti-inflammatory cytokines, in particular of IL-4 [4, 10, 14], are produced/expressed by RA synovial T cells in vivo, the mechanisms for this are still unclear. At least three main hypotheses can be considered to explain the lack of IL-4-producing cells in the RA synovium: (i) rapid egress of precursors of IL-4-producing cells from the synovium, perhaps due to a lack of retention signals, though no data exist to support this hypothesis; (ii) selective recruitment of IFN-
-producing T cells, which may be driven by selected chemokine expression [21, 22], with consequent suppression of IL-4; and (iii) a dysregulated immune response secondary to the general cytokine milieu (not only IFN-
) in the joint, whereby different subsets of dendritic cells may play a key role through the production of growth factors [23], which would lead to the skewing of recruited peripheral blood T cells towards the Th1 phenotype, with a secondary imbalance of the Th1/Th2 ratio [4, 5, 2427]. This last hypothesis appears to be the most convincing, and it is supported by the evidence that IL-4-producing cells can be generated from synovial tissue T lymphocytes once they have been removed from the suppressive joint environment, indicating that not all infiltrating T cells are Th1-polarized [27].
However, another important factor that might explain the low level of detection of Th2 cytokines in the joint is that synovial material is evaluated almost exclusively during disease flares. Hence, by definition, little is known about the cytokine production profile during remission phases. Thus, it is possible that, during these phases, the production of Th2-type cytokines potentially increases, but this remains undocumented. In this setting, therefore, the identification of markers selectively associated with Th2-type cytokine-secreting cells that can be measured at all stages of the disease may provide a useful tool to better understand the basic dysfunction that eventually leads to the predominance of Th1 cells in RA.
A number of molecules have been associated with Th2-type cytokine production. Memory CD4+ T cells expressing L-selectin (CD62L) appear to produce more IL-4 and less IFN-
in comparison with CD62L-negative CD4+ T cells [28]. However, IL-10 is produced in similar amounts by human L-selectin-positive and -negative memory CD4+ T subpopulations, making it difficult to discriminate Th2 from Th1 cells [28]. Mature memory CD4+ T cells bearing the CD45RBdim/CD27 phenotype are characterized by the production of IL-4 in normal conditions, but there is evidence to suggest that they lose this characteristic cytokine pattern when recruited in the RA joint [2931]. More recently, it has been reported that specific chemokine receptors are expressed preferentially by human Th1 and Th2 cells [32]. With regard to the Th2 phenotype, CCR3 (a promiscuous receptor for various chemokines, including RANTES (regulated upon activation, normal T-cell expressed and secreted chemokine), MCP (monocyte chemotactic protein)-2, -3 and -4, eotaxin, CCR4 [receptor for the dendritic cell-derived chemokine thymus and activation-regulated chemokine (TARC)] and CCR8 appear to be associated with Th2-like T cells in some stages of their differentiation/activation process and to be involved in the development of Th2 response [3336]. However, chemokine receptors do not represent stable phenotypic markers; for this reason, and because of their low level of membrane expression, attempts to use them to identify Th1 or Th2 cells in vitro and in vivo have proved extremely controversial [37, 38].
More recently, the selective expression on human Th2 cells of a novel surface molecule, the chemoattractant receptor-homologous molecule CRTH2, has been described [39]. CRTH2 is an orphan receptor closely related to the N-formyl peptide receptor and the C5a receptor that is expressed not only on Th2 cells but also on basophils and eosinophils [40]. Although CRTH2 appears to fulfil the requirements for a reliable marker of human Th2 cells [41], the very low percentage of CRTH2+ cells described in both normal and Th2-driven diseases makes the utilization of this molecule for the purpose of quantifying Th2-cell activity in vivo extremely difficult.
Another problem related to the identification of Th2 markers in humans, contrary to the mouse, is represented by the absence of a clear-cut Th1/Th2 dichotomy [42, 43]. As a consequence, it is difficult to identify a molecule exclusively expressed by Th1 or Th2 cells. In contrast, it appears more reliable to use a surface marker whose expression is strictly dependent on the synthesis of a particular cytokine selectively produced by Th1 or Th2 cells. In this respect, the observation that the expression of CXCR4 (receptor for the lymphoid chemokine CXCL12/SDF-1) is up-regulated by IL-4 and down-regulated by IL-12/IFN-
initially looked very promising [44]. However, it was demonstrated subsequently that CXCR4 expression is not limited to Th2 cells but is also expressed at high levels by Th1 cells in the rheumatoid joint [45, 46].
Another molecule modulated in a similar fashion by IL-4 and IFN-
is CD30, a member of the TNF receptor family molecule [47, 48]. Contrary to CXCR4, CD30 has been found to be expressed only in association with the Th0/Th2-type response in vitro [49], making it a potential specific marker for this subset of T cells. Although the expression of CD30 on the surface of T cells is rather scant, the cleavage and release of the extracellular segment of the molecule after cell activation offers the possibility of monitoring CD30+ cell activity in the tissues by measuring the soluble (s) form of the molecule in biological fluids [47, 5052]. Following early reports of high serum levels of sCD30 in a number of Th2- but not Th1-polarized disorders [5358], it was proposed that CD30 is indeed specifically associated with Th2-oriented diseases [59, 60]. However, this assumption has been challenged subsequently, at least in vivo, by studies showing increased serum levels of sCD30 also in some disorders characterized by a predominant Th1 response [6166]. This apparent paradox has been addressed by our group in a number of studies that appear to confirm that the high serum level of sCD30 found in Th1-type diseases, such as RA, mirrors the activity of CD30+ cells secreting counter-regulatory cytokines, such as IL-4 and IL-10, at the sites of inflammation [61, 67, 68]. This has led us recently to propose the counter-regulatory paradigm, in which the activation of CD30+ cells in Th1-driven diseases would be part of the homeostatic mechanisms involved in counteracting inflammation [69]. This hypothesis is supported by a number of observations. First, particularly during the first phases of RA synovitis, clonal analysis of synovial CD30+ T-cells demonstrates the production of large amounts of IL-4 and IL-10 [68]. Secondly, sCD30 serum levels are inversely correlated to C-reactive protein in patients with very early RA [67]. Thirdly, in early RA, high levels of sCD30, hence high levels of CD30-mediated anti-inflammatory activity, were associated with a better response to treatment [67]. The measurement of sCD30, therefore, may represent a good, although indirect, index of the involvement of T cells in anti-inflammatory activity in the joint related to the combined secretion of IL-4 and IL-10, at least in the initial phases of the disease.
The inverse correlation between sCD30 and C-reactive protein, however, is not found in patients with long-standing RA [61, 67]. A simple explanation for this could be that, in long-standing RA, the disease might have reached a point of no return, with an overwhelming Th1 dominance that drives inflammation independently of the activity of CD30+ cells. However, it is also important to consider the pleomorphic action of IL-4 itself and the different effects that result from the interplay of IL-4 with other cytokines, in particular IL-10. As mentioned above, in addition to anti-inflammatory properties, IL-4 may also have proinflammatory activity [20]. Likewise, IL-10, besides its down-regulatory function, has a number of actions that are potentially harmful to the RA synovium, including the ability to stimulate the B-cell production of immunoglobulin (Ig) M and IgG and, in particular, of IgM rheumatoid factor [7072]. Indeed, we have demonstrated that sCD30 levels also correlate with serum levels of rheumatoid factor [61]. Thus, the protective effect against joint damage seems to be exerted essentially by the combined action of IL-4 and IL-10; not only do the two cytokines act synergistically, but also they each protect against the harmful effects of the other [20]. Although RA synovial CD30+ cells can produce both IL-4 and IL-10, the decline in the amount of IL-10 secreted by CD30+ cells over time may lead to an imbalance between the two cytokines and a reduction in the maximal anti-inflammatory effect exerted by their combined activity [20, 68, 69]. This could contribute to the predominance of Th1 cells seen in long-standing RA, with important repercussions for the persistence of inflammation and joint destruction [7375]. However, the development of powerful biological therapies for RA, which are undoubtedly associated with clinical improvement, may be related at least in part to re-dressing the Th1Th2 balance within the joint [76]. Increased Th2 activity is suggested, for example, by the increased production of autoantibodies in these patients [77, 78]. In this context, therefore, it would be interesting to monitor Th0/Th2 activity by measuring sCD30 levels in patients undergoing cytokine blockade and/or immunosuppressive therapies.
In conclusion, in RA, synovial CD30+ cells would be part of the Th2-type response acting as a homeostatic mechanism to counterbalance the proinflammatory events driven by Th1-type cells/cytokines. They would exert their anti-inflammatory activity through the synergistic action of IL-4 and IL-10. The possibility of evaluating such activity by simply measuring the levels of circulating sCD30, in all phases of the disease (relapse, remission) and in response to therapy, may offer better insight into the mechanisms involved in controlling disease evolution.
Notes
Correspondence to: R. Gerli, Dipartimento di Medicina Clinica e Sperimentale, Sezione di Medicina Interna e Scienze Oncologiche, Centro per lo Studio delle Malattie Reumatiche, Policlinico di Monteluce, I-06122 Perugia, Italy. 
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