ABERRANT CYTOKINE REGULATION IN MACROPHAGES FROM YOUNG AUTOIMMUNE-PRONE MICE - EVIDENCE THAT THE INTRINSIC DEFECT IN MRL MACROPHAGE IL-1 EXPRESSION IS TRANSCRIPTIONALLY CONTROLLED

We have reported that, when compared to macrophages from normal strain s, macrophages from the autoimmune-prone MRL and NZB mouse strains dem onstrate dramatically reduced IL-1 expression in response to LPS. In M RL mice, this is an intrinsic defect which is unmodified by age, the p rogression of disease, or the presence of the Ipr gene. Here we report that the key events leading to aberrant IL-1 expression appear to be transcriptional, based on the following three sets of findings. (1) Nu clear run-on analysis demonstrates that the patterns of IL-1 transcrip tion in MRL/+ and BALB/c macrophages are distinct, as the former is cl early more transient. The reduction in MRL/+ IL-1 transcription coinci des with a reduction in the levels of nuclear NF-B-kappa and precedes a drop in IL-1 mRNA steady-state levels. (2) Reduced levels of IL-1 tr anscripts are found in both nuclear and cytosolic fractions of MRL/+ m acrophages, arguing against faulty IL-1 mRNA transport into the cytoso l as a contributing factor in the establishment of this defect. (3) In the presence of actinomycin D, the rate of RNA degradation is similar in MRL/+ and BALB/c macrophages. Moreover, in vitro RNA decay assays demonstrate that even in the absence of metabolic inhibitors, there is no evidence for an accelerated decay of IL-1 mRNA during exposure to lysates isolated from MRL/+ vs BALB/c macrophages. Taken together, the se findings argue that transcription is the predominant level at which this striking example of cytokine dysregulation is controlled.