Aberrant cytokine expression and autocrine regulation characterize macrophages from young MRL super(+/+) and NZB/W F sub(1) lupus-prone mice

• Published in: The Journal of immunology (1950) Vol. 159; no. 11; pp. 5610 - 5619
• Main Authors: Alleva, D G, Kaser, S B, Beller, DI
• Format: Journal Article
• Language: English
• Published: 01.12.1997
• ISSN: 0022-1767

We investigated whether macrophages (M\g?\) from young, lupus-prone MRL super(+/+) and NZB/W F sub(1) mice expressed common defects in immunoregulatory cytokine production. Endotoxin-activated M\g?\ from both strains, obtained well before disease signs, had a markedly reduced capacity to maintain IL-1 production compared with M\g?\ from normal strains (BALB/c, A/J, and C57BL/6). M\g?\ 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 M\g?\ from lupus-prone mice, demonstrating a stimulus-specific induction of the proinflammatory defects. These studies also revealed that M\g?\ 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 M\g?\ 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 M\g?\ (and perhaps other cells of the innate immune system) may provide valuable insights into intrinsic functional defects associated with systemic autoimmunity.