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B Expression and Binding to the IL-12 p40 Promoter1
Arthritis Section, Department of Medicine, Boston University Medical Center, Boston MA 02118
Intrinsic defects in macrophage (M
) cytokine production
characterize many autoimmune-prone mouse strains. Aberrant levels of
IL-12, for example, are produced by M 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-
B site in the IL-12 p40 promoter, whereas binding
patterns to Ets and CCAAT enhancer binding protein/
sites
were normal. In particular, the heightened production of IL-12 by NOD
M 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/+ M 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.
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