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

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

doi:10.4049/jimmunol.176.2.1244

Abstract

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-kappaB. 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-kappaB 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-kappaB with H. hepaticus.

Highlights

Why The JI? Submit online. Rapid Reviews! 30 days* from submission to initial decision No Triage! Every submission reviewed by practicing scientists Fast Publication! 4 weeks from acceptance to publicatio
We have found that Helicobacter hepaticus (Hh) is a poor inducer of IL-12 p40 expression in macrophages derived from wild-type (WT) mice that are resistant to colitis, Hh does induce robust expression of IL-12 p40 in macrophages derived from mice that are susceptible to Hh-induced colitis, including mice lacking IL-10
To determine whether Tpl-2 was necessary for Hh-induced ERK activation, bone marrow-derived macrophages (BMDM) were harvested from Tpl-2-deficient mice, and MEK and ERK activation was evaluated after challenge with Hh (Fig. 1b)

Summary

Abbreviations used in this paper

Helicobacter hepaticus; BMDM, bone marrow-derived macrophage; WT, wild type. It has been demonstrated that the ability of ERK1/2 to inhibit IL-12 p40 expression depends upon the induction of the immediate-early gene c-fos [14, 15], which has been suggested to be a direct inhibitor of IL-12 p40 gene transcription [17] These observations raise the question of whether Hh is able to induce activation of ERK1/2 and its target c-Fos, and whether these events have a role in preventing robust expression of IL-12 p40. The release of Tpl-2 from p105 is induced by phosphorylation of Tpl-2 at Thr290 [21, 22] and is supported by the signal-dependent degradation of p105 [23, 24] These observations have led us to hypothesize that p105 and Tpl-2 may be involved in mediating ERK activation in response to Hh and, if correct, may provide a mechanistic explanation for the higher expression of IL-12 p40 observed after Hh challenge of p50/p105-deficient macrophages. P50/p105- and Tpl-2-dependent ERK activation plays a central role in regulating IL-12 p40 expression after Hh challenge

Materials and Methods

Results

Discussion