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Rheumatology 2001; 40: 474-475
© 2001 British Society for Rheumatology
Letters to the Editor |
Correlation of circulating interleukin 16 with proinflammatory cytokines in patients with rheumatoid arthritis
Department of Internal Medicine IV, Friedrich Schiller University of Jena and
1 Roche Diagnostics GmbH, Germany
SIR, Interleukin 16 (IL-16), also known as lymphocyte chemoattractant factor, is generally considered to play a decisive role in most immune and inflammatory responses. But contradictory reports exist for the importance of IL-16 in the regulation of rheumatoid synovitis. CD4 and CD8 T-lymphocytes, monocytes, eosinophils, epithelial cells and fibroblasts found in the rheumatoid arthritis (RA) synovium were found to produce IL-16. After binding to its receptor molecule, CD4, IL-16 induces different kinds of intracellular signal transduction and expression of T-cell surface molecules [1], resulting in the stimulation of CD4+ T-cells and monocytes, causing them both to migrate into inflamed tissues and stimulating their proliferation. On the other hand, the binding of IL-16 to CD4 leads to suppression of T-cell receptor (TCR)/CD3-mediated activation, resulting in T-cell anergy, as observed in the mixed lymphocyte reaction [2]. These contradictory functions of IL-16 are reflected in different reports about the role of IL-16 in RA. Klimiuk et al. [3] described an anti-inflammatory activity of synovial tissue-infiltrating CD8+ T-cells mediated by the release of IL-16. In contrast, Franz et al. [4] found elevated IL-16 levels in the synovial fluid correlating with parameters of inflammation and they demonstrated synovial fibroblasts as a source of IL-16 using in situ hybridization experiments.
The aim of this study was to look for correlations between circulating levels of IL-16 and known proinflammatory cytokines in RA patients and controls, in order to provide more evidence that IL-16 acts as a mediator promoting inflammation. Non-heparinized blood was collected from 48 patients who fulfilled the 1987 revised American College of Rheumatism criteria for RA [5] and 40 healthy controls. Characteristics of these subjects are given in Table 1
. Cytokine levels were determined using commercial ELISA systems from Roche Molecular Biochemicals, Mannheim, Germany (IL-16), R&D Systems, Minneapolis, MN, USA [IL-1ß, tumour necrosis factor 
(TNF-), IL-6, the soluble IL-6 receptor (sIL-6R) and the soluble TNF receptors 1 and 2 (sTNFR1 and -R2)] and Immunotech International, Marseille, France (sIL-2R). For statistical analysis we used the Mann–Whitney U-test and the Spearman rank correlation coefficient.
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In RA, serum IL-16 and serum TNF-
, IL-6, sIL-2R and sTNFR1 and -R2 levels were increased significantly compared with non-RA controls. In RA patients and controls, there were no significant differences in cytokine levels with respect to age or sex. Moreover, in RA patients, there was a close correlation between serum IL-16 level and serum levels of IL-1ß, TNF-, IL-6, sIL-2R and sTNFR1 and -R2, but not between IL-16 and sIL-6R. In RA patients, disease duration was correlated positively with X-ray disease status and negatively with erythrocyte sedimentation rate (ESR), but not with any cytokine or cytokine receptor tested in this study. Levels of IL-16, IL-6, TNF-, sIL-2R and sTNFR1 and -R2 were positively correlated with ESR and C-reactive protein (Table 1
). Results obtained were in agreement with the proinflammatory role of IL-16 as discussed elsewhere. Enhanced expression of IL-16-mRNA and an increased number of CD4+ T-cells were found recently in acute and chronic skin lesions of patients with atopic dermatitis and in allergen-induced late-phase nasal responses [6]. Moreover, Lee et al. [7] found that elevated levels of IL-16 correlated positively with the systemic lupus erthematosus disease activity index. IL-16-mediated T-cell abnormalities, such as activation and clonal anergy, related to a breakdown of self-tolerance, have been reported repeatedly for this representative autoimmune disease [8]. IL-16 serum levels correlate with soluble CD4, which is shed from the the CD4 T-cell surface by activation [7]. These findings indicate an initial stimulation of CD4+ cells in the presence of increased IL-16 levels, estimating the proinflammatory effect of IL-16.
Interesting similarities were observed between IL-16- and HIV-1-induced activation of CD4+ lymphocytes. IL-16, which is slightly elevated in HIV-1 infection, and HIV-1-gp120 both bind to the CD4 molecule, resulting in expression of HLA class II molecules, the production of IL-2 and the induction of T-cell anergy. In agreement with this, autoimmune-related phenomena, including arthritis, have been described repeatedly in HIV-1 infection [9].
There are hints of a proinflammatory action of IL-16 from the mechanism of its generation. Stimulation of IL-16-secreting cells leads to cleavage of the C-terminal region of a preformed pro-IL-16 by caspase-3, resulting in the release of biologically active IL-16 [10]. Proteinases of the caspase family, known as IL-1ß-converting enzymes, also process pro-IL-1ß into active IL-1ß, although there are no significant sequence similarities between the precursors of these two cytokines [10]. Rheumatoid synovial tissue synthesizes large amounts of IL-1ß, which is known to be a key factor in the destruction of cartilage and bone.
The positive correlations that we found between IL-16 and other mediators that are important in promoting inflammatory responses (TNF-, IL-6 and sIL-2R) may be an additional argument for the proinflammatory role of IL-16 in RA. The elevated levels of sTNFR seem to be a compensatory response, as discussed elsewhere. In conclusion, IL-16 appears to be an interesting cytokine for further research and novel therapeutic approaches in this inflammatory disease.
Notes
Correspondence to: J Kaufmann, Department of Internal Medicine IV, Friedrich-Schiller-University of Jena, D-07740 Jena, Germany. 
References
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- Klimiuk PA, Goronzy JJ, Weyand CM. IL-16 as an anti-inflammatory cytokine in rheumatoid synovitis. J Immunol1999;162:4293–9.
[Abstract/Free Full Text] - Franz J, Kolb SA, Hummel KM, Lahrtz F, Neidhart M, Aicher WK et al. Interleukin-16, produced by synovial fibroblasts, mediates chemoattraction for CD4+ T lymphocytes in rheumatoid arthritis. Eur J Immunol1998;28:2661–71.[Web of Science][Medline]
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- Lee S, Kaneko H, Sekigawa I, Tokano Y, Takasaki Y, Hashimoto H. Circulating interleukin-16 in systemic lupus erythematosus. Br J Rheumatol1998;37:1334–7.
[Abstract/Free Full Text] - Via CS, Handwerger BS. B-cell and T-cell function in systemic lupus erythematosus. Curr Opin Rheumatol1993;5:570–4.[Medline]
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- Zhang Y, Center DM, Wu H, Cruikshank WW, Yuan J, Andrews DW et al. Processing and activation of pro-interleukin-16 by caspase-3. J Biol Chem1997;273:1144–9.
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