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Aberrant cytokine expression and autocrine regulation characterize macrophages from young MRL+/+ and NZB/W F1
D G Alleva1, S B Kaser, D I Beller
1Evans Memorial Department of Clinical Research, Boston University Medical Center, MA 02118-2393, USA. dgalleva@bu.edu
Abstract:
We investigated whether macrophages (Mphi) from young, lupus-prone MRL+/+ and NZB/W F1 mice expressed common defects in immunoregulatory cytokine production. Endotoxin-activated Mphi from both strains, obtained well before disease signs, had a markedly reduced capacity to maintain IL-1 production compared with Mphi from normal strains (BALB/c, A/J, and C57BL/6). Mphi from lupus-prone mice showed similar defects in IL-6 and TNF-alpha production, which preceded the IL-1 defect. In fact, defective TNF-alpha production appeared to be responsible for aberrant expression of the other cytokines because this defect was the first to be expressed, and treatment with exogenous TNF-alpha reduced the extent of defective IL-1 and IL-6. These "proinflammatory" cytokine defects appeared to be selective because the anti-inflammatory cytokine IL-10 was not expressed aberrantly in the lupus-prone strains. For this reason, and because anti-IL-10 mAb treatment did not correct defective proinflammatory cytokine production, IL-10 did not appear to be responsible for these defects. IFN-gamma was able to normalize TNF-alpha production in Mphi from lupus-prone mice, demonstrating a stimulus-specific induction of the proinflammatory defects. These studies also revealed that Mphi from the three normal strains studied here maintain a precise inverse relationship between levels of TNF-alpha and IL-10, a relationship not seen in Mphi from lupus-prone strains. These findings reveal shared elements of cytokine dysregulation in the two principal animal models of multigenic lupus, and suggest that the study of Mphi (and perhaps other cells of the innate immune system) may provide valuable insights into intrinsic functional defects associated with systemic autoimmunity.
Insights
Macrophages from lupus-prone mice exhibit early defects in pro-inflammatory cytokine production, specifically TNF-alpha, impacting IL-1 and IL-6. These findings offer insights into innate immune system dysfunction in systemic autoimmunity.
Area of Science:
- Immunology
- Autoimmunity
- Innate Immune System
Background:
- Systemic lupus erythematosus (SLE) is a complex autoimmune disease.
- Macrophages (Mphi) play a critical role in immune regulation.
- Early functional defects in Mphi may contribute to lupus pathogenesis.
Purpose of the Study:
- To investigate common immunoregulatory cytokine production defects in macrophages from young, lupus-prone mouse models.
- To identify early molecular and cellular dysfunctions preceding overt disease in lupus.
Main Methods:
- Comparison of endotoxin-activated Mphi from lupus-prone (MRL+/+ and NZB/W F1) and normal (BALB/c, A/J, C57BL/6) mice.
- Quantification of interleukin-1 (IL-1), IL-6, tumor necrosis factor-alpha (TNF-alpha), and IL-10 production.
- Assessment of cytokine dysregulation using exogenous cytokine treatments and neutralizing antibodies.
Main Results:
- Mphi from lupus-prone mice showed reduced IL-1, IL-6, and TNF-alpha production before disease onset.
- Defective TNF-alpha production was the earliest defect and appeared responsible for aberrant IL-1 and IL-6 levels.
- Interferon-gamma (IFN-gamma) normalized TNF-alpha production, indicating stimulus-specific defects.
- Normal Mphi exhibited an inverse TNF-alpha/IL-10 relationship, absent in lupus-prone Mphi.
Conclusions:
- Shared cytokine production defects in macrophages from distinct lupus models suggest intrinsic immune system dysfunction.
- Early dysregulation of pro-inflammatory cytokines by macrophages may be a key factor in lupus development.
- Targeting macrophage function or innate immune pathways could offer novel therapeutic strategies for SLE.