Tribbles-1 as a Novel Biomarker of Chronic Antibody-Mediated Rejection

Ashton‐Chess, Joanna; Giral, Magali; Mengel, Michael; Renaudin, Karine; Foucher, Yohann; Gwinner, Wilfried; Braud, Christophe; Dugast, Emilie; Quillard, Thibaut; Thébault, Paméla; Chiffoleau, Elise; Braudeau, Cécile; Charreau, Béatrice; Soulillou, Jean‐Paul; Brouard, Sophie

doi:10.1681/asn.2007101056

Cited by 74 publications

(55 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…39,40) In contrast, little is known about the mechanisms regulating TRB1 induction. TRB1 is up-regulated during inflammatory events such as chronic antibody-mediated rejection of transplanted organs 21) and chronic inflammation of atherosclerotic arteries 41) ; and is also induced in response to mitochondrial dysfunction, independent of production of reactive oxygen species (ROS) or metabolic stress. 42) This induction mainly occurs under transcriptional control with ERK1/2 activation.…”

Section: Discussionmentioning

confidence: 99%

“…19) TRB1 is also a critical factor for adipose tissue maintenance and suppression of metabolic disorders because it controls differentiation of tissue-resident M2-like macrophages. 20) Members of the Tribbles family (TRB1, TRB2 and TRB3) are relatively highly expressed in immune tissues and cells, 21,22) but their functions and regulation in the immune system are not completely clear. TRB1 is a negative regulator of C/EBPβ protein expression and modulates C/ EBPβ-dependent gene expression in Toll like receptor (TLR)-mediated signaling 23) ; and a recent study showed that TRB1 is strongly expressed in Tregs, as a novel binding partner of Foxp3.…”

Section: )mentioning

confidence: 99%

See 1 more Smart Citation

Positive Regulation of Interleukin-2 Expression by a Pseudokinase, Tribbles 1, in Activated T Cells

Miyajima

Itoh

Inoue

et al. 2015

Biological & Pharmaceutical Bulletin

View full text Add to dashboard Cite

Tribbles 1 (TRB1), a member of the Tribbles family, is a pseudokinase that is conserved among species and implicated in various human diseases including leukemia, cardiovascular diseases, and metabolic disorders. However, the role of TRB1 in the immune response is not understood. To evaluate this role, we examined regulation of TRB1 expression and the function of TRB1 in interleukin-2 (IL-2) induction in Jurkat cells, a human acute T cell leukemia cell line. We found that TRB1 was strongly induced by phorbol 12-myristate 13-acetate (PMA) and ionomycin in these cells. IL-2 expression was induced in Jurkat cells activated by PMA and ionomycin; however, knockdown of TRB1 resulted in decreased induction of IL-2. TRB1 null Jurkat cells established using the CRISPR/Cas9 system also showed reduction of IL-2 expression on PMA/ ionomycin stimulation. TRB1 knockdown also markedly inhibited IL-2 promoter activation. To determine the mechanism of the stimulatory effect on IL-2 induction, we focused on histone deacetylases (HDACs), and found that HDAC1 preferentially interacts with TRB1. TRB1 suppressed the interaction of HDAC1 with nuclear factor of activated T cells 2 (NFAT2), which is a crucial transcription factor for IL-2 induction. These results indicate that TRB1 is a positive regulator of IL-2 induction in activated T cells. Key words Tribbles 1 (TRB1); interleukin-2 (IL-2); histone deacetylase (HDAC); nuclear factor of activated T cells (NFAT)Interleukin-2 (IL-2) is a central factor in the immune system that affects various lymphocyte subsets during differentiation and in immune responses and homeostasis. 1) IL-2 is crucial for differentiation of CD4 + T cells into defined effector T cell subsets following antigen-mediated activation and for development and peripheral expansion of regulatory T (Treg) cells, which promote self-tolerance by suppressing T cell responses. For CD8 + T cells, IL-2 signaling optimizes effector T cell generation and differentiation into memory cells. 2) IL-2 is produced primarily in activated CD4+ T cells and is regulated at the mRNA level by signals from the T cell receptor (TCR) and CD28.3) Regulation of IL-2 transcription has been well characterized, and the nuclear factor of activated T cells (NFAT) and activator protein-1 (AP-1) transcription factors have been shown to be essential for inducible IL-2 expression in activated T cells. [4][5][6] Activation of NFATs is mainly regulated by calcium and calcineurin, while that of AP-1 is regulated by other pathways, including the protein kinase C (PKC) and Ras-mitogen-activated protein kinase (MAPK) pathways. In response to TCR stimulation, phospholipase C γ1 (PLCγ1) is phosphorylated and activated, and subsequent hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2) by PLCγ1 produces inositol trisphosphate (IP3) and diacylglycerol (DAG) as second messengers. IP3 mediated Ca 2+ release from the endoplasmic reticulum (ER) and sequential entry of extracellular Ca 2+ through calcium release-activated Ca 2+ (CRAC) channels activates calcineu...

show abstract

Section: Discussionmentioning

confidence: 99%

Section: )mentioning

confidence: 99%

Positive Regulation of Interleukin-2 Expression by a Pseudokinase, Tribbles 1, in Activated T Cells

Miyajima

Itoh

Inoue

et al. 2015

Biological & Pharmaceutical Bulletin

View full text Add to dashboard Cite

show abstract

“…These data also underline how important it will be for future studies of gene expression in transplantation to be performed on large cohorts allowing for potential confounding factors to be taken into account when evaluating diagnostic, predictive, or mechanistic biomarkers. Analyzing other markers of CAMR, such as Tribbles-1 28 or TLR4, 29 markers of acute rejection, such as the cytotoxic molecules Perforin and Fas-L, 12,30 or other regulatory T cell-associated markers, such as GITR, 31 could help to better understand the pathogenesis of CAMR and contribute to its diagnosis.…”

Section: Discussionmentioning

confidence: 99%

Regulatory, Effector, and Cytotoxic T Cell Profiles in Long-Term Kidney Transplant Patients

Ashton‐Chess

Dugast²,

Colvin³

et al. 2009

Journal of the American Society of Nephrology

Self Cite

View full text Add to dashboard Cite

Animal studies have suggested a potential role for regulatory T cells (Tregs) in allograft tolerance, but these FOXP3ϩ cells seem to be an inherent component of acute rejection (AR) in human recipients of renal transplants. The balance between regulatory cells and effector/cytotoxic cells may determine graft outcome; this balance has not been described for chronic allograft injury. We investigated the expression of key regulatory, effector, and cytotoxic transcripts (i.e., FOXP3, T-bet, and granzyme B, respectively) in the grafts and peripheral blood of long-term-surviving renal transplant patients. We found that, whereas neither intragraft nor peripheral blood FOXP3 or T-bet mRNA could distinguish between rejection and nonrejection status, granzyme B (GrzB) mRNA could: It was significantly increased in the graft and significantly decreased in the peripheral blood of patients with chronic antibody-mediated rejection (CAMR). Quantifying peripheral blood GrzB mRNA demonstrated potential to aid in the noninvasive diagnosis of CAMR. In summary, these data affirm GrzB as a marker not only for AR but also for CAMR. In addition, we identified several previously unreported clinical or demographic factors influencing regulatory/effector/cytotoxic profiles in the peripheral blood, highlighting the necessity to consider confounding variables when considering the use of potential biomarkers, such as FOXP3, for diagnosis or prognosis in kidney transplantation.

show abstract

“…Among previously defined pharmacological responses, this application identified NFkB signaling pathway as the top 'toxicological' response contained within the expression dataset (p = 0.000943; Table 5). Finally, to investigate whether the over-representation of pro-inflammatory pathways in SRL recipients could be attributed to subclinical allograft rejection, we compared between CSA and SRL patients the expression of a group of genes previously proposed as blood transcriptional biomarkers of kidney allograft rejection: PRF1, GZMB, FASLG, CD40LG, IFNG, IL4, IL5, IL6, PSMB10, TLR4, MYD88 and TRIB1 (34)(35)(36)(37)(38)(39)(40). None of these genes, however, were found to be differentially expressed between SRL and CSA recipients.…”

Section: Recipients Treated With Srl Monotherapy Exhibit Increased Numentioning

confidence: 99%

Comparative Transcriptional and Phenotypic Peripheral Blood Analysis of Kidney Recipients Under Cyclosporin A or Sirolimus Monotherapy

Brouard

Puig-Pey

Lozano

et al. 2010

American Journal of Transplantation

View full text Add to dashboard Cite

Due to its low level of nephrotoxicity and capacity to harness tolerogenic pathways, sirolimus (SRL) has been proposed as an alternative to calcineurin inhibitors in transplantation. The exact mechanisms underlying its unique immunosuppressive profile in humans, however, are still not well understood. In the current study, we aimed to depict the in vivo effects of SRL in comparison with cyclosporin A (CSA) by employing gene expression profiling and multiparameter flow cytometry on blood cells collected from stable kidney recipients under immunosuppressant monotherapy. SRL recipients displayed an increased frequency of CD4 + CD25highFoxp3 + T cells. However, this was accompanied by an increased number of effector memory T cells and by enrichment in NFkB-related pro-inflammatory expression pathways and monocyte and NK cell lineage-specific transcripts. Furthermore, measurement of a transcriptional signature characteristic of operationally tolerant kidney recipients failed to detect differences between SRL and CSA-treated recipients. In conclusion, we show here that the blood transcriptional profile induced by SRL monotherapy in vivo does not resemble that of operationally tolerant recipients and is dominated by innate immune cells and NFkB-related pro-inflammatory events. These data provide novel insights on the complex effects of SLR on the immune system in clinical transplantation.

show abstract

Tribbles-1 as a Novel Biomarker of Chronic Antibody-Mediated Rejection

Cited by 74 publications

References 45 publications

Positive Regulation of Interleukin-2 Expression by a Pseudokinase, Tribbles 1, in Activated T Cells

Positive Regulation of Interleukin-2 Expression by a Pseudokinase, Tribbles 1, in Activated T Cells

Regulatory, Effector, and Cytotoxic T Cell Profiles in Long-Term Kidney Transplant Patients

Comparative Transcriptional and Phenotypic Peripheral Blood Analysis of Kidney Recipients Under Cyclosporin A or Sirolimus Monotherapy

Contact Info

Product

Resources

About