Translation control: a multifaceted regulator of inflammatory response

Abstract

A robust innate immune response is essential to the protection of all vertebrates from infection, but it often comes with the price tag of acute inflammation. If unchecked, a runaway inflammatory response can cause significant tissue damage, resulting in myriad disorders, such as dermatitis, toxic shock, cardiovascular disease, acute pelvic and arthritic inflammatory diseases, and various infections. To prevent such pathologies, cells have evolved mechanisms to rapidly and specifically shut off these beneficial inflammatory activities before they become detrimental. Our review of recent literature, including our own work, reveals that the most dominant and common mechanism is translational silencing, in which specific regulatory proteins or complexes are recruited to cis-acting RNA structures in the untranslated regions of single or multiple mRNAs that code for the inflammatory protein(s). Enhancement of the silencing function may constitute a novel pharmacological approach to prevent immunity-related inflammation.

FIGURE 1

Pro- and anti-inflammatory axis of IL-10 depends on translation regulation. Left, Inflammatory stimuli activate p38 MAPK that disengages ARE binding proteins and derepresses the translation of inflammatory proteins. In a global anti-inflammatory role, IL-10 negatively regulates this process by abrogating the activation by p38 MAPK. Right, Occupancy of the adenosine receptors by its ligands relieves the imposed translational repression of IL-10 mRNA and activates the synthesis of IL-10 protein (blue circles). As a proinflammatory molecule, IL-10 stimulates ferritin translation by removing the translational repressor (the iron response element-binding protein) from 5′ UTR. Overproduction of ferritin causes sequestration of available iron (rust-colored circles) for bone marrow, leading to the characteristic anemia of inflammation.

FIGURE 2

Chemoattraction of T lymphocytes by RANTES is under translation control. RFLAT, a transcription factor of RANTES, is silenced at the level of translation in unstimulated cells by 4E-BP. Phosphorylation of 4E-BP by mTOR promotes dissociation of 4E-BP, allowing assembly of the translation initiation factors (eIFs) on RFLAT mRNAs. This activates the translation of RFLAT protein and promotes the transcription of RANTES gene. Expression of RANTES (blue circles) is required for the chemoattraction of T lymphocytes to the sites of injury.

FIGURE 3

A translationally regulated enzyme 15-lipoxygenase controls neutrophil influx. A neutrophil (magenta) is recruited to the tissue from the lumen. This process is mediated by leukotriene B4 synthesized from arachidonate and catalyzed by 5-lipoxygenase within the neutrophil. The recruitment of neutrophil in the tissue is depicted to bring in arachidonate that produces lipoxin using translationally regulated enzyme, 15-lipoxygenase. Note that this enzyme is different from the 5-lipoxygenase within the neutrophil. The regulation requires recruitment of the hRNPK complex (green) to DICE, a novel RNA element in the 3′ UTR of 15-lipoxygenase mRNA that can block 60S ribosomal subunit joining and inhibit translation. Tissue lipoxin (blue circles), generated by 15-lipoxygenase, exits and blocks further neutrophil influx. DICE, differentiation induced control element.

FIGURE 4

Control of the IFN-γ axis and the GAIT paradigm of translational silencing. IL-18, an epithelial cell-derived factor, induces IFN-γ in T cells. The synthesis of both IL-18 and IFN-γ is under translational control by sequence elements at the 5′ UTR of their cognate mRNAs (left). In myeloid cells (such as macrophages), IFN-γ induces the initial inflammatory signal that is eventually silenced by an ordered assembly of the GAIT complex (subunits in yellow). Formation of GAIT complex requires the release of its subunit proteins from their parental complex triggered by phosphorylation events (phosphate groups in red). The binding of silencing-competent GAIT complex at the GAIT elements of the 3′ UTRs of the mRNAs (the members of the posttranscriptional operon) encoding inflammatory proteins directly blocks translation by intercepting the recruitment of 40S ribosomal subunit. Translational silencing of a group of inflammatory proteins by the GAIT pathway resolves inflammation.