Immunosuppressant FK506 induces interleukin-6 production through the activation of transcription factor nuclear factor (NF)-kappa(B). Implications for FK506 nephropathy.
FK506 is a powerful immunosuppressive drug currently in use that inhibits the activation of several transcription factors (nuclear factor (NF)-AT and NF-kappaB) critical for T cell activation. We show here that, contrary to the situation in T cells, FK506 activates transcription factor NF-kappaB in nonlymphoid cells such as fibroblasts and renal mesangial cells. We further show that FK506 induces NF-kappaB-regulated IL-6 production in vitro and in vivo, in particular in kidney. IL-6 has been shown previously to produce renal abnormalities in vivo, such as mesangioproliferative glomerulonephritis. Similar renal abnormalities were also observed in FK506-treated animals. These results thus suggest a causal relationship between FK506-induced NF-kappaB activation/IL-6 production and some of FK506-induced renal abnormalities.
Muraoka
K
K
Department of Molecular Pathology, Cancer Research Institute, School of Medicine, Kanazawa University, 13-1 Takaramachi, Kanazawa, Ishikawa 920, Japan.
Fujimoto
K
K
Sun
X
X
Yoshioka
K
K
Shimizu
K
K
Yagi
M
M
Bose
H
H
Miyazaki
I
I
Yamamoto
K
K
D000818:Animals; D001483:Base Sequence; D004268:DNA-Binding Proteins / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D005920:Glomerular Mesangium / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D006801:Humans; D020672:I-kappa B Proteins; D007150:Immunohistochemistry; D007166:Immunosuppressive Agents / Q000494:pharmacology* / Q000633:toxicity; D015850:Interleukin-6 / Q000032:analysis / Q000096:biosynthesis* / Q000652:urine; D007668:Kidney / Q000187:drug effects / Q000276:immunology / Q000473:pathology*; D007739:L Cells; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008969:Molecular Sequence Data; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015345:Oligonucleotide Probes; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D016559:Tacrolimus / Q000494:pharmacology* / Q000633:toxicity
D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; D007166:Immunosuppressive Agents; D015850:Interleukin-6; D016328:NF-kappa B; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; D015345:Oligonucleotide Probes; D011993:Recombinant Fusion Proteins; D000072000:NF-KappaB Inhibitor alpha; D016559:Tacrolimus