More MS news articles for June 2002

Aberrant Production of IL-12 by Macrophages from Several Autoimmune-Prone Mouse Strains Is Characterized by Intrinsic and Unique Patterns of NF-kappaB Expression and Binding to the IL-12 p40 Promoter

J Immunol 2002 Jul 1;169(1):581-6
Liu J, Beller D.
Arthritis Section, Department of Medicine, Boston University Medical Center, Boston MA 02118.

Intrinsic defects in macrophage (Mphi) cytokine production characterize many autoimmune-prone mouse strains.

Aberrant levels of IL-12, for example, are produced by Mphi isolated from young mice prone to lupus (MRL and NZB/W) and diabetes (nonobese diabetic (NOD)) well before the appearance of disease signs.

Evaluation of the possible mechanism(s) underlying the abnormal regulation of IL-12 in these strains revealed novel patterns of Rel family protein binding to the unique p40 NF-kappaB site in the IL-12 p40 promoter, whereas binding patterns to Ets and CCAAT enhancer binding protein/beta sites were normal.

In particular, the heightened production of IL-12 by NOD Mphi is associated with elevated levels of the trans-activating p50/c-Rel (p65) complex compared with the nonfunctional p50/p50 dimer.

Conversely, the dramatically impaired production of IL-12 by both NZB/W and MRL/+ Mphi is associated with a predominance of p50/p50 and reduced p50/c-Rel(p65) binding.

Mechanistically, the unique pattern seen in the lupus strains reflects elevated p50 and reduced c-Rel nuclear protein levels.

In NOD extracts, the level of c-Rel is elevated compared with that in lupus strains, but not when compared with that in normal A/J.

However, the extent of c-Rel tyrosine phosphorylation noted in NOD extracts is more than double that seen in any other strain.

Levels of p65 were similar in all strains tested.

These findings reveal that a common mechanism, involving dysregulation of c-Rel and p50, may be used to determine the aberrant IL-12 levels that have the potential to predispose specific mouse strains to systemic or organ-specific autoimmunity.