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

• Published in: Journal of Immunology 2006-01, Vol.176 (2), p.1244-1251
• Main Authors: Tomczak, Michal F., Gadjeva, Mihaela, Wang, Yan Yan, Brown, Ketorah, Maroulakou, Ioanna, Tsichlis, Philip N., Erdman, Susan E., Fox, James G., Horwitz, Bruce H.
• Format: Article
• Language: English
• Subjects: Helicobacter hepaticus
• ISSN: 0022-1767; 1550-6606; 1365-2567
• DOI: 10.4049/jimmunol.176.2.1244

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-κB. 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-κB 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-κB with H. hepaticus.