Cytokine disequilibrium induced by

Parry, Sebbag, Feldmann & Brennan A (1997) J. Immunol 158: 3673

Parry, Sebbag, Feldmann & Brennan A (1997) J. Immunol 158: 3673

T cell gested a differential regulation of monocyte-derived cytokine production by Th1-like vs Th2-like cells. Thus CD4+ Th1 clones induced high levels of IL-ip production by THP-1 monocytes whereas Th2 clones induced higher levels of IL-lra, which implies that Th1 cells are pro-inflammatory, whereas the Th2 cells are anti-inflammatory.

Are Rheumatoid T Cells Cytokine Activated?

The hypothesis that RA T cells mimic Tck cells is attractive since T cells found in rheumatoid arthritis synovium have several unusual characteristics. They are relatively small, noncycling, but have features of activation, with over half expressing HLA class II, VLA antigens, CD25 and CD69 (reviewed in [14, 15]). T cell receptor analysis has not revealed a consistent pattern: oligoclonal and dominant clones or responses to putative auto-antigens have not been easy to reproduce (reviewed in [16]). Based on these features, and their low capacity to produce T cell derived cytokines, it has been proposed that T cells in the joint are not involved in the later stages of the disease [17]. However, our data suggests that they are involved in disease pathology through contact-dependent activation of macrophages to induce TNF. The environment of the RA synovium is conducive to the generation of Tck cells, as it is rich in the relevant cytokines. Unutmaz et al. described the generation of bystander-activated T cells from normal PBMCs with the cocktail IL-2, IL-6 and TNFa [18]; this may work via the reported upregulation of IL-2Ra (CD25) by IL-6 and TNF. We found that IL-15 could, by itself, mimic the IL-6/TNFa/IL-2 cocktail used to activate Tck [11]. This is likely to be due to the suppression of IL-15 high-affinity R in the absence of activation. IL-15 is of particular interest as it is found in RA synovium [19] and can activate peripheral blood T cells to induce TNFa synthesis in U937 cells or adherent RA synovial cells in a contact-dependent manner [20,21].

It is likely that other cognate cell-to-cell interactions occur in the synovial joint and contribute to the disease pathology observed in RA. These interactions include the endothelial cell-T cell and the fibroblast-T cell interactions [22]. During early stages of inflammation, there is a large cellular infiltration from the blood to the synovial joint, where interactions between T cells and vascular endothelium drive further inflammation and extravasation and infiltration, mediated by the expression of cell adhesion molecules, chemokines and cytokines [22-25]. In addition, the earliest infiltrating cells, neutrophils, can be activated by contact-mediated interaction with T cells as determined by the ability of these neutrophils to be primed for respiratory burst by FMLP [26]. As the pathology of RA progresses to chronic inflamma tion and pannus forms at the cartilage-pannus junction (CPJ), the interactions between T cells and fibroblasts or macrophages is likely to become more important. Recently, the interaction between stimulated T cells and dermal fibroblasts or synoviocytes has been shown to induce MMP-1 (collagenase) and TIMP-1 with an imbalance in favour of the pro-inflammatory MMP-1 [27], and also inhibiting the synthesis of types I and III collagen by fibroblast cells [28].

Studies undertaken thus far have documented the potent stimulatory activity of T cells on monocyte cytokine production during the pathology of RA. However, there are abundant T cells and monocytes in the peripheral circulation, which have the potential to physically interact with each other, but this does not seem to induce cytokine production. This may be due to the serum factor, apo A-1 which acts to prevent monocyte activation [29]. The capacity of apo A-1 to inhibit T cell-mediated macrophage activation suggests that this molecule or its derivatives may have a useful anti-inflammatory therapeutic effect in chronic inflammatory diseases such as RA.

Cell Surface Molecules of Potential Relevance

As contact-dependent signals have been demonstrated to be of importance, attention has focused upon which are the important signals. There are multiple candidate molecules on the surface of cells that may be able to mediate these functions. Antibody blocking of specific surface interaction molecules has been reported to suppress the induction of monocyte cytokine synthesis. These include CD69, LFA-1 [8, 30], CD44 [31], CD45 [32], CD40 [33], membrane TNF [12], and SLAM [34]. There are technical difficulties in these experiments as blocking cell adhesion molecules on T or monocytic cells would prevent the cells interacting and would not obviously indicate that these ligation interactions were involved in monocyte activation.

Our studies have demonstrated that T cells activated through the T cell receptor complex induced monocyte IL-10 synthesis. This was partially dependent on endogenous TNFa and IL-1, and T cell membrane TNFa was an important contact-mediated signal [12,35]. However, IL-10 synthesis still occurred when TNFa and IL-1 were neutralized, suggesting that there are TNF/IL-1-independent signals required for IL-10 synthesis, which remain to be identified.

Of particular interest are members of the TNF/TNF-R family, which include CD40, CD27, CD30, 0X-40, and LTp. The ligands of these TNF-R molecules have been described to be upregulated upon T cell activation and in addition CD40L, 4-1BB, CD27L, CD30 have been described to be released as soluble molecules after activation [36-39]. The interaction between CD40L

and CD40 has been described to be of importance for inducing both IL-1 and IL-12 synthesis following T cell interaction with monocytes [33, 40] and more recently to mediate IL-10 production by human microglial cells upon interaction with anti-CD3-stimulated T cells [41]. In addition, we have shown recently that CD40L-CD40 interaction mediates cognate induction of macrophage IL-10 [42].

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Arthritis Relief and Prevention

Arthritis Relief and Prevention

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