Immunosuppressant FK506 induces interleukin-6 production through the activation of transcription factor nuclear factor (NF)-kappa(B). Implications for FK506 nephropathy.

Muraoka, Keiichi; Fujimoto, Kayoko; Sun, Xiangao; Yoshioka, Katsuji; Shimizu, Kohichi; Yagi, Minoru; Bose, Henry R.; Miyazaki, Itsuo; Yamamoto, Ken

doi:10.1172/jci118690

Cited by 60 publications

(33 citation statements)

References 32 publications

(29 reference statements)

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“…Interestingly, FK506 has recently been reported to induce NF-B activation and concomitant proinflammatory cytokine expression in renal mesangial cells and fibroblasts. 79 The correlation of increasing NF-B activity shown in KCs with higher tacrolimus trough levels in the current study support evidence of a tacrolimus-induced activation of NF-B. Further investigations with a larger sample size are warranted to confirm the preliminary observations of heightened intragraft NF-B activation observed under tacrolimus versus CsA.…”

Section: Discussionsupporting

confidence: 76%

Intragraft localization of activated nuclear factorκB in recurrent hepatitis C virus disease following liver transplantation

et al. 2000

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Nuclear factor B (NF-B) is activated during viral infection and isAn estimated 170 million people worldwide and nearly 4 million people in the United States alone are infected with the hepatitis C virus (HCV). 1,2 Up to 85% of the individuals infected with HCV develop a chronic disease course associated with an increased risk of cirrhosis and hepatocellular carcinoma. 1,3 Currently, end-stage liver disease secondary to HCV infection is the leading indication for orthotopic liver transplantation (OLTx) in the United States. 4 Recurrence of HCV infection after OLTx of HCV patients is universal and associated with HCV viremia and high intragraft HCV antigen levels. 5-9 More than half of OLTx patients transplanted because of HCV-related disease will develop histopathologic evidence of chronic hepatitis 10-12 and some will develop a severe form of fibrosing cholestatic hepatitis associated with progressive allograft failure, 13,14 whereas others will develop allograft cirrhosis 15 and de novo hepatocellular carcinoma. 16 The specific pathogenetic mechanisms contributing to recurrent HCV infection and disease progression in immunocompromised transplant patients remain ill defined. Worse yet, the limited understanding of the pathogenesis of HCV infection in immunocompetent individuals provides little insight into the development of a successful therapeutic strategy for transplant recipients infected with the HCV.Substantial evidence has implicated a pivotal role for liver-specific immune-mediated mechanisms that include the production of inflammatory mediators and activation of host effector cells, in the development and progression of the liver injury associated with chronic HCV infection in immunocompetent individuals. [17][18][19][20] Moreover, recent investigations have documented a low number of apoptotic hepatocytes in HCV-infected liver tissue, 21-23 perhaps as a critical mechanism whereby uninhibited viral replication can occur. 24,25 The transcription factor nuclear factor B (NF-B), initially identified as an inducer of B-cell-specific gene expresssion, 26 is known to regulate the HCV-specific expression of several inflammatory mediator genes and inhibition of apoptotic cell death, which may influence the replication of HCV and the

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Section: Discussionsupporting

confidence: 76%

Intragraft localization of activated nuclear factorκB in recurrent hepatitis C virus disease following liver transplantation

et al. 2000

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“…Interstitial fibrosis caused by CsA is associated with increased expression of TGF-␤1 (56), and TGF-␤1 is responsive to induction by IL-1 in macrophages, which activates NF-B and several other transcription factors (57). IL-6 has been reported to contribute to nephrotoxicity (58,59), and FK506 induces IL-6 production in fibroblasts through the activation of NF-B (60). A role for FK506-induced NF-B activation in inducing nephrotoxicity was shown by a study in rats of chronic FK506 nephropathy, in which the NF-B inhibitor pyrrolidine dithiocarbamate reduced FK506-induced monocyte/macrophage infiltration, tubular injury, and intestinal fibrosis, which are hallmarks of nephrotoxicity (61).…”

Section: Discussionmentioning

confidence: 99%

Calcineurin Negatively Regulates TLR-Mediated Activation Pathways

Kang

Kusler

Otsuka

et al. 2007

The Journal of Immunology

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In innate immunity, microbial components stimulate macrophages to produce antimicrobial substances, cytokines, other proinflammatory mediators, and IFNs via TLRs, which trigger signaling pathways activating NF-κB, MAPKs, and IFN response factors. We show in this study that, in contrast to its activating role in T cells, in macrophages the protein phosphatase calcineurin negatively regulates NF-κB, MAPKs, and IFN response factor activation by inhibiting the TLR-mediated signaling pathways. Evidence for this novel role for calcineurin was provided by the findings that these signaling pathways are activated when calcineurin is inhibited either by the inhibitors cyclosporin A or FK506 or by small interfering RNA-targeting calcineurin, and that activation of these pathways by TLR ligands is inhibited by the overexpression of a constitutively active form of calcineurin. We further found that IκB-α degradation, MAPK activation, and TNF-α production by FK506 were reduced in macrophages from mice deficient in MyD88, Toll/IL-1R domain-containing adaptor-inducing IFN-β (TRIF), TLR2, or TLR4, whereas macrophages from TLR3-deficient or TLR9 mutant mice showed the same responses to FK506 as those of wild-type cells. Biochemical studies indicate that calcineurin interacts with MyD88, TRIF, TLR2, and TLR4, but not with TLR3 or TLR9. Collectively, these results suggest that calcineurin negatively regulates TLR-mediated activation pathways in macrophages by inhibiting the adaptor proteins MyD88 and TRIF, and a subset of TLRs.

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“…We previously showed that FK506 induces IB␣ degradation and NF-B activation in nonlymphoid cells such as renal mesangial cells and fibroblasts. We further showed that, as a result of NF-B activation by FK506, interleukin-6 production is induced in the kidney, suggesting the possibility of a causal relationship between the FK506-induced NF-B activation/IL-6 production and some FK506-induced renal abnormalities (18). However, little is known about how FK506 induces IB␣ degradation in nonlymphoid cells.…”

Section: Nuclear Factor B (Nf-b)mentioning

confidence: 84%

“…Induces the Degradation of IB␣ and IB␤-To analyze the effects of FK506 stimulation on IB degradation, HAtagged IB␣ expression vectors were transfected into L-TK cells, which were most efficient in FK506-mediated NF-B activation (18). Cells were then treated with IL-1 or FK506 for different periods of time.…”

Section: Fk506mentioning

confidence: 99%

Immunosuppressant FK506 Activates NF-κB through the Proteasome-mediated Degradation of IκBα

Zhang

Sun

Muraoka

et al. 1999

Journal of Biological Chemistry

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The immunosuppressant FK506 activates NF-B through IB␣ degradation in nonlymphoid cells. In the present study, we analyzed mechanisms by which FK506 induces IB␣ degradation. We found that FK506 induces the degradation of both IB␣ and IB␤ and that the time courses of the FK506-induced degradation are quite different from degradation induced by interleukin 1 (IL-1). Despite this difference, FK506-induced IB␣ degradation was dependent on the N-terminal Ser-32 and Ser-36 phosphorylation sites and was mediated by proteasomes, as is the case for IL-1-induced IB␣ degradation. We further showed that FK506 induces weak and slow phosphorylation of IB␣ at Ser-32. However, unlike IL-1-induced degradation, IKK-1 and IKK-2 were not activated significantly nor was FK506-induced IB␣ degradation dependent on the N-terminal ubiquitination sites (Lys-21 and Lys-22). These results therefore indicate that FK506 and IL-1 utilize similar but distinct mechanisms to induce the phosphorylation and degradation of IB␣. Nuclear factor B (NF-B)1 is a transcription factor that plays an important role in inducing the expression of diverse cellular genes, such as for various cytokines, cell surface receptors, and acute-phase proteins. It is a heterodimer mainly composed of the p50 and RelA proteins, but there might be a considerable heterogeneity in its composition in various cell types, because of the presence of p50/RelA-related proteins (p52, c-Rel, and RelB), which share extensive homology in their N-terminal DNA-binding/dimerization regions. These proteins are now known as the NF-B/Rel/Dorsal transcription factor family, as they are also related to the Drosophila maternal morphogen gene, dorsal. An unusual feature of this family is that they exist in the cytoplasm in an inactive form complexed with a family of inhibitor proteins termed IB (IB␣, IB␤, and IB⑀). A variety of stimuli, including virus infection, bacterial lipopolysaccharides, double-stranded RNA, phorbol esters, UV radiation, oxidative stress, and inflammatory cytokines such as interleukin-1 (IL-1) and tumor necrosis factor-␣ (TNF-␣) activate NF-B through the proteolytic degradation of IB and the subsequent translocation of NF-B to the nucleus, where it activates target genes (1-3).The prototypic and best-studied of the IBs is IB␣, which is phosphorylated at its N-terminal two serine residues (Ser-32 and Ser-36) prior to degradation, when cells are exposed to appropriate NF-B activators (4 -6). This phosphorylation triggers the ligation of multiple ubiquitin molecules to nearby lysine residues (Lys-21 and Lys-22), leading to the subsequent degradation of the protein by proteasomes (6 -9). The signalinduced phosphorylation of IB␣ is therefore a critical step in NF-B activation and has been investigated intensively. Recently, two closely related IB kinases (IKKs), termed IKK-1 and IKK-2, have been identified and cloned. Both kinases directly phosphorylate Ser-32 and Ser-36 of IB␣ and their activities are stimulated by IL-1 and TNF-␣ treatment (10 -14). In addition, pp90rsk kinase...

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Immunosuppressant FK506 induces interleukin-6 production through the activation of transcription factor nuclear factor (NF)-kappa(B). Implications for FK506 nephropathy.

Cited by 60 publications

References 32 publications

Intragraft localization of activated nuclear factorκB in recurrent hepatitis C virus disease following liver transplantation

Intragraft localization of activated nuclear factorκB in recurrent hepatitis C virus disease following liver transplantation

Calcineurin Negatively Regulates TLR-Mediated Activation Pathways

Immunosuppressant FK506 Activates NF-κB through the Proteasome-mediated Degradation of IκBα

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