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Defective Activation of ERK in Macrophages Lacking the p50/p105 Subunit of NF-B Is Responsible for Elevated Expression of IL-12 p40 Observed after Challenge with Helicobacter hepaticus¹

Michal F. Tomczak^*, Mihaela Gadjeva^*, Yan Yan Wang^*, Ketorah Brown^*, Ioanna Maroulakou, Philip N. Tsichlis, Susan E. Erdman, James G. Fox and Bruce H. Horwitz^2,*,

^* Immunology Research Division, Department of Pathology, Brigham and Women’s Hospital, Boston, MA 02115; Molecular Oncology Research Institute, Tufts New England Medical Center, Boston, MA 02111; Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA 02139; and Division of Emergency Medicine, Children’s Hospital, Boston, MA 02115

Helicobacter hepaticus is an enterohepatic Helicobacter species that induces lower bowel inflammation in susceptible mouse strains, including those lacking the p50/p105 subunit of NF-B. H. hepaticus-induced colitis is associated with elevated levels of IL-12 p40 expression, and p50/p105-deficient macrophages express higher levels of IL-12 p40 than wild-type macrophages after challenge with H. hepaticus. However, the molecular mechanisms by which the p50/p105 subunit of NF-B suppresses IL-12 p40 expression have not yet been elucidated. In this study we have demonstrated that H. hepaticus challenge of macrophages induces ERK activation, and this event plays a critical role in inhibiting the ability of H. hepaticus to induce IL-12 p40. Activation of ERK requires both p50/p105 and the MAPK kinase kinase, Tpl-2. Inhibition of the induction of IL-12 p40 by ERK was independent of c-Rel, a known positive regulator of IL-12 p40. Instead, it was linked to the induction of c-Fos, a known inhibitor of IL-12 p40 expression. These results suggest that H. hepaticus induces ERK activation by a pathway dependent upon Tpl-2 and p105, and that activation of ERK inhibits the expression of IL-12 p40 by inducing c-Fos. Thus, a defect in ERK activation could play a pivotal role in the superinduction of IL-12 p40 observed after challenge of macrophages lacking the p50/p105 subunit of NF-B with H. hepaticus.

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