Background/Purpose IL-6 has been found increased in SLE, while CRP, which is directly stimulated by IL-6, usually remains low. We therefore analyzed the IL-6/ IL-6 R system in SLE.

Methods Peripheral blood mononuclear cells (PBMC) of 41 SLE patients and 71 healthy individuals (HC) were prepared. CRP and disease activity (by ECLAM) were recorded. Serum IL-6 and sIL-6R were measured by ELISA. For determining the percentages of CD126 and CD130 positive cells, PBMC were directly stained with PE-labelled or control antibodies. For analyzing IL-6 induced Stat3 phosphorylation, PBMC were stimulated with rhIL-6 (250 ng/ml) for 15 min, fixed with formaldehyde (2%), permeabilized with methanol (80%), and stained with PE-labelled antibodies to phosphorylated Stat3 (pStat3) or control antibodies. For in vitro experiments on the influence on receptor expression, healthy PBMC were incubated for 24 hours with or without the addition of IL-6, IL-10, tumor necrosis factor (TNF), interferon-α (IFNα), or combinations of these cytokines. Stained cells were immediately analyzed on a Becton Dickinson FACSCalibur fluorocytometer, gating for lymphocytes. As a semiquantitative measure of pStat3 contents mean fluorescence intensity (mfi) was used.

Results SLE serum IL-6 levels (median (range)) (3.6 (0.69-69.3) pg/ml) were significantly (p<0.0001) higher than those of HC (0.9 (0.12-10.5) pg/ml) and correlated with disease activity (Spearman r= 0.41, p= 0.01). CRP was slightly increased in SLE (1.8 (1.0-40.8) pg/ml vs 0.8 (0.3-4.8) pg/ml for HC, p<0.0001). The percentage of CD126+ lymphocytes (mean±SD) was decreased in SLE (48±16 % vs. 61±11% for HC p<0.0001). In line with reduced receptor expression, the IL-6 induced increase in pStat3 was significantly reduced in SLE (Δmfi 14.2 (-19.91-37.15) vs. HC (Δmfi 18.8 (-2.2-50.06), p=0.004). In a mirror image to the membrane receptor, soluble IL6 receptor (sIL-6R) serum levels were increased in SLE (42.1 (24.1-109.6) ng/ml as compared to (38.6 (16.4-80.5) ng/ml in HC, p=0.05). Moreover, sIL-6R was negatively correlated with the percentage of CD126+ lymphocytes (Spearman r=-0.35, p=0.03). In vitro stimulation assays showed that the reduction in CD126+ cells could be mimicked by combinations of IL-6 with either IFNα (-39± 13%) or TNF (-16± 6%).  

Conclusion In SLE, combinations of IFNα or TNF with IL-6, all of which are increased in response to immune complexes, apparently lead to shedding of the cellular IL-6 receptor CD126 and thus increase sIL-6R. This shifts the IL-6 system towards trans-signalling, directing the effects of the increased IL-6 away from conventional signalling, as responsible for increased CRP, and towards effects on cells carrying gp130 only.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/a-shift-towards-trans-signalling-explains-relatively-low-crp-despite-an-active-interleukin-6-il-6il-6-receptor-il-6r-system-in-sle/