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Exogenous IL-10 and IL-4 down-regulate IL-6 production by SLE-derived PBMC
M Linker-Israeli1, M Honda, R Nand
1Department of Medicine, Cedars-Sinai Medical Center Research Institute, California 90048, USA.
Abstract:
The elevated expression of IL-6 and IL-10 may have an important role in SLE pathogenesis. IL-6 production by normal monocytes can be inhibited by IL-10, and it has been suggested that SLE monocytes are refractory to this negative signal. To examine this possibility, the effects of regulatory factors on IL-6 expression by SLE PBMC (N = 51) were compared to effects on control PBMC (N = 21). We found that (1) exogenous rIL-10 and rIL-4 mediated reduction of constitutive and lectin-induced IL-6 in monocytes of SLE patients as effectively as that of controls; (2) IL-6 mRNA decay was significantly delayed in SLE with active disease (P < 0.001); (3) adding rIL-10 or neutralizing endogenous IL-1 beta and TNF-alpha down-regulated IL-6 mainly by destabilizing IL-6 transcripts, whereas exogenous IL-4 and TGF beta 1 down-regulated IL-6 transcriptionally; (4) time kinetics and levels of IL-10 were lower than those of IL-6 and IL-1 beta. Thus, contrary to a previous report, IL-6 production by SLE PBMC responds normally to regulatory signals, and the IL-6 overexpression in SLE may be due, at least in part, to the kinetics and availability of regulatory cytokines.
Insights
Systemic lupus erythematosus (SLE) involves elevated interleukin-6 (IL-6). SLE monocytes respond normally to regulatory signals, suggesting altered cytokine kinetics, not refractoriness, drives IL-6 overexpression in this disease.
Area of Science:
- Immunology
- Rheumatology
- Molecular Biology
Background:
- Elevated interleukin-6 (IL-6) and interleukin-10 (IL-10) are implicated in systemic lupus erythematosus (SLE) pathogenesis.
- Previous studies suggested SLE monocytes might be resistant to IL-10's inhibitory effects on IL-6 production.
Purpose of the Study:
- To investigate the regulatory mechanisms of IL-6 expression in peripheral blood mononuclear cells (PBMCs) from SLE patients compared to healthy controls.
- To determine if SLE PBMCs exhibit altered responses to regulatory cytokines like IL-10, IL-4, and TGF-beta 1.
Main Methods:
- Compared the effects of exogenous recombinant IL-10 (rIL-10) and IL-4 (rIL-4) on IL-6 production in SLE (N=51) and control (N=21) PBMCs.
- Analyzed IL-6 mRNA decay rates and the impact of cytokine neutralization (IL-1 beta, TNF-alpha) and exogenous cytokines on IL-6 transcription and stability.
- Measured the time kinetics and levels of IL-6, IL-10, and IL-1 beta.
Main Results:
- SLE PBMCs showed normal reduction of IL-6 production in response to exogenous rIL-10 and rIL-4, similar to controls.
- IL-6 mRNA decay was significantly delayed in active SLE patients (P < 0.001).
- IL-10 and IL-1 beta levels and kinetics were lower than IL-6 levels, suggesting potential imbalances in regulatory cytokine availability.
Conclusions:
- Contrary to prior suggestions, SLE PBMCs do not appear refractory to IL-10-mediated IL-6 inhibition.
- IL-6 overexpression in SLE may stem from delayed IL-6 mRNA decay and suboptimal kinetics/availability of regulatory cytokines like IL-10 and IL-1 beta.
- These findings highlight the importance of cytokine dynamics in SLE pathogenesis.
