Posttranscriptional Modulation of Cytokine Production in T Cells for the Regulation of Excessive Inflammation by TFL

Abstract

Posttranscriptional machinery regulates inflammation and is associated with autoimmunity as well as tumorigenesis in collaboration with transcription factors. We previously identified the tumor suppressor gene transformed follicular lymphoma (TFL) on 6q25 in a patient with follicular lymphoma, which transformed into diffuse large B cell lymphoma. TFL families have a common RNase domain that governs macrophage-mediated inflammation. In human peripheral blood, TFL is dominantly expressed at the glycine- and tryptophan-rich cytoplasmic processing bodies of T lymphocytes, and it is persistently upregulated in activated T cells. To address its physiological role, we established TFL−/− mice in which TFL−/− lymphocytes proliferated more rapidly than TFL+/+ upon stimulation with inappropriate cytokine secretion, including IL-2, IL-6, and IL-10. Moreover, TFL inhibited the synthesis of cytokines such as IL-2, IL-6, IL-10, TNF-α, and IL-17a by 3′ untranslated region RNA degradation. Experimental autoimmune encephalitis induced in TFL−/− mice demonstrated persistent severe paralysis. CNS-infiltrated CD4+ T cells in TFL−/− mice contained a higher proportion of Th17 cells than did those in TFL+/+ mice during the resolution phase, and IL-17a mRNA levels were markedly increased in TFL−/− cells. These results suggest that TFL may play an important role in attenuating local inflammation by suppressing the infiltration of Th17 cells in the CNS during the resolution phase of experimental autoimmune encephalitis. TFL is a novel gradual and persistent posttranscriptional regulator, and the TFL-driven attenuation of excessive inflammation could contribute to recovery from T cell–mediated autoimmune diseases.

Monocyte Chemotactic Protein-induced Protein 1 and 4 Form a Complex but Act Independently in Regulation of Interleukin-6 mRNA Degradation

“…However, MCPIP4-deficient mice did not show gross developmental defects (21). On the other hand, emerging evidence suggests that MCPIP1 and MCPIP4 have some similar effects on the regulation of IL-6 mRNA degradation and endothelial inflammation (21,35,36). Taken together, these studies suggest that both MCPIP1 and MCPIP4 may involve in the regulation of inflammatory cytokine production.…”

“…In the gene knock-out mouse models, MCPIP1-deficient mice developed severe and complex inflammatory phenotypes including splenomegaly, lymphadenopathy, multi-organ inflammatory cell infiltration, and premature death (2,11). However, MCPIP4-deficient mice did not show gross developmental defects (21). On the other hand, emerging evidence suggests that MCPIP1 and MCPIP4 have some similar effects on the regulation of IL-6 mRNA degradation and endothelial inflammation (21,35,36).…”

“…Mouse anti-Zc3h12d (MCPIP4) monoclonal antibody was kindly provided by Dr. T. Matsui (20,21). Rabbit anti-MCPIP4 antibody was purchased from Proteintech.…”

“…2C, MCPIP1 protein was detected as a single band around 72 kDa (migrated behind theoretical protein size). The specificity of anti-MCPIP4 monoclonal antibody was determined previously (20,21). To determine whether MCPIP1 and MCPIP4 are colocalized in cells, HeLa cells were co-transfected with Flag-MCPIP1 and EGFP-MCPIP4 and visualized by staining with anti-Flag and Alexa Fluor596-labeled second antibody.…”

“…The role of MCPIP4 in vivo seems overlapped but less important than MCPIP1. For example, MCPIP4-null mice showed pretty normal phenotypes under normal condition, but exhibited more activated lymphocytes upon stimulation (21).…”