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Dysregulated cytokine expression in vivo in prediseased and diseased autoimmune-prone MRL mice
J M Fitzpatrick1, J S Koh, D Hartwell
1Renal Section, Department of Medicine, Boston University Medical Center, Massachusetts 02118, USA.
Abstract:
Macrophages (mø) from prediseased autoimmune-prone MRL/ + and MRL/lpr mice produce markedly decreased levels of IL-1 in vitro in response to LPS. In contrast, tissues from diseased MRL/lpr mice overexpress IL-1 in vivo. To determine whether IL-1 underproduction in the MRL strains is solely an in vitro phenomenon, we compared in vivo cytokine mRNA expression from prediseased age-matched MRL/ + and MRL/lpr mice to that from normal BALB/c and C3HeB/FeJ mice. Like mø in vitro, whole organ RNA from the spleen, liver, and kidney of MRL/ + and MRL/lpr mice showed down-regulation of IL-1 RNA following intraperitoneal injection of LPS. This abnormality in inducible IL-1 expression was present in all MRL mice, irrespective of disease stage or the presence of the lpr gene. On the other hand, only diseased MRL/lpr mice displayed elevated and constitutive expression of IL-1 in their livers and kidneys. We suggest that inducible expression is most indicative of the intrinsic, or genetic, capacity of cells to produce cytokine, whereas constitutive expression reflects extracellular disease-related inflammatory stimuli present only in the diseased MRL/lpr strains. By restricting our studies to prediseased MRL mice, we have tried to eliminate the effects of disease and to focus on the predisposing genetic background. The existence both in vitro and in vivo of a defect in inducible IL-1 expression by prediseased MRL mice suggests that the molecular abnormality underlying this defect may be a part of this predisposing background to autoimmunity.
Insights
Prediseased autoimmune-prone mice show reduced inducible interleukin-1 (IL-1) production both in vitro and in vivo. This defect in IL-1 gene expression may be a key genetic factor predisposing to autoimmunity.
Area of Science:
- Immunology
- Genetics
- Autoimmunity
Background:
- Macrophages (mø) from autoimmune-prone MRL strains exhibit reduced in vitro IL-1 production.
- In contrast, diseased MRL/lpr mice show in vivo IL-1 overexpression.
Purpose of the Study:
- To investigate if IL-1 underproduction in MRL strains is an in vitro-specific phenomenon.
- To analyze in vivo cytokine mRNA expression in prediseased MRL mice compared to normal controls.
Main Methods:
- Comparison of in vivo IL-1 mRNA expression in prediseased MRL/ + and MRL/lpr mice versus BALB/c and C3HeB/FeJ mice.
- Intraperitoneal lipopolysaccharide (LPS) injection to assess inducible IL-1 RNA expression in spleen, liver, and kidney.
- Analysis of constitutive IL-1 expression in diseased MRL/lpr mice.
Main Results:
- Prediseased MRL mice demonstrated down-regulated IL-1 RNA in spleen, liver, and kidney post-LPS injection, mirroring in vitro findings.
- This inducible IL-1 expression defect was consistent across all MRL mice, regardless of disease status or the 'lpr' gene.
- Elevated and constitutive IL-1 expression was observed only in the livers and kidneys of diseased MRL/lpr mice.
Conclusions:
- Inducible IL-1 expression reflects intrinsic cellular capacity, while constitutive expression indicates disease-related inflammation.
- The defect in inducible IL-1 expression in prediseased MRL mice, observed both in vitro and in vivo, suggests a genetic basis.
- This molecular abnormality may be a crucial component of the genetic predisposition to autoimmunity in MRL strains.