Abstract
Proinflammatory responses induced by Toll-like receptors (TLRs) are dependent on the activation of the NF-ĸB and mitogen-activated protein kinase (MAPK) pathways, which coordinate the transcription and synthesis of proinflammatory cytokines. We demonstrate that BCL-3, a nuclear IĸB protein that regulates NF-ĸB, also controls TLR-induced MAPK activity by regulating the stability of the TPL-2 kinase. TPL-2 is essential for MAPK activation by TLR ligands, and the rapid proteasomal degradation of active TPL-2 is a critical mechanism limiting TLR-induced MAPK activity. We reveal that TPL-2 is a nucleocytoplasmic shuttling protein and identify the nucleus as the primary site for TPL-2 degradation. BCL-3 interacts with TPL-2 and promotes its degradation by promoting its nuclear localization. As a consequence, Bcl3-/- macrophages have increased TPL-2 stability following TLR stimulation, leading to increased MAPK activity and MAPK-dependent responses. Moreover, BCL-3-mediated regulation of TPL-2 stability sets the MAPK activation threshold and determines the amount of TLR ligand required to initiate the production of inflammatory cytokines. Thus, the nucleus is a key site in the regulation of TLR-induced MAPK activity. BCL-3 links control of the MAPK and NF-ĸB pathways in the nucleus, and BCL-3-mediated TPL-2 regulation impacts on the cellular decision to initiate proinflammatory cytokine production in response to TLR activation.
Highlights
Proinflammatory responses induced by Toll-like receptors (TLRs) are dependent on the activation of the NF-ĸB and mitogenactivated protein kinase (MAPK) pathways, which coordinate the transcription and synthesis of proinflammatory cytokines
On further analysis we observed that, in addition to inhibiting the expression of NF-κB–regulated proinflammatory genes, BCL-3 limits the TLR-inducible transcription of a number of immediate/early genes that have previously been shown to rely on mitogen-activated protein kinase (MAPK) activity for expression [21]
Stimulation of Bone marrow-derived macrophages (BMDMs) with other TLR ligands (CpG, PAM3CSK4, or Poly[I:C]) or TNFα led to increased expression of MAPK target genes in Bcl3−/− cells compared to WT cells (SI Appendix, Fig. S1)
Summary
Proinflammatory responses induced by Toll-like receptors (TLRs) are dependent on the activation of the NF-ĸB and mitogenactivated protein kinase (MAPK) pathways, which coordinate the transcription and synthesis of proinflammatory cytokines. We demonstrate that BCL-3, a nuclear IĸB protein that regulates NF-ĸB, controls TLR-induced MAPK activity by regulating the stability of the TPL-2 kinase. BCL-3–mediated regulation of TPL-2 stability sets the MAPK activation threshold and determines the amount of TLR ligand required to initiate the production of inflammatory cytokines. BCL-3 links control of the MAPK and NF-ĸB pathways in the nucleus, and BCL-3–mediated TPL-2 regulation impacts on the cellular decision to initiate proinflammatory cytokine production in response to TLR activation. Active TPL-2 is highly unstable and is rapidly degraded by the proteasome [14, 16] This is the primary mechanism limiting TLR-induced MAPK activation. The MAPK pathway is ultrasensitive; that is, activation in response to in-
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