Emerging role of IκBζ in inflammation: Emphasis on psoriasis

Abstract

Psoriasis is a chronic inflammatory disorder affecting skin and joints that results from immunological dysfunction such as enhanced IL‐23 induced Th‐17 differentiation. IkappaB‐Zeta (IκBζ) is an atypical transcriptional factor of the IκB protein family since, contrary to the other family members, it positively regulates NF‐κB pathway by being exclusively localized into the nucleus. IκBζ deficiency reduces visible manifestations of experimental psoriasis by diminishing expression of psoriasis‐associated genes. It is thus tempting to consider IκBζ as a potential therapeutic target for psoriasis as well as for other IL23/IL17‐mediated inflammatory diseases. In this review, we will discuss the regulation of expression of NFKBIZ and its protein IκBζ, its downstream targets, its involvement in pathogenesis of multiple disorders with emphasis on psoriasis and evidences supporting that inhibition of IκBζ may be a promising alternative to current therapeutic managements of psoriasis.

Transcriptome Analysis of Diffuse Large B-Cell Lymphoma Cells Inducibly Expressing MyD88 L265P Mutation Identifies Upregulated CD44, LGALS3, NFKBIZ, and BATF as Downstream Targets of Oncogenic NF-κB Signaling

“…Similarly, nuclear factor of kappa light polypeptide gene enhancer in B cells inhibitor zeta (NFKBIZ), a member of the nuclear I-kappa-B family, stabilizes the promoter binding of other transcription regulators and is involved in the transcriptional control of inflammation, cell proliferation, and survival [ 109 , 110 , 111 ]. Depending on the context, the IκBζ protein can promote or inhibit gene expression and the activation of signaling pathways involved in producing inflammatory molecules [ 110 , 112 ].…”

The roles and mechanisms of the NF-κB signaling pathway in tendon disorders

“…IκB is a specific inhibitor of NF-κB. The IκB proteins in mammalian contain seven members: IκBα, IκBβ, IκBε, IκBδ, Bcl-3, IκBξ, and IκBNS ( Table 2 ) ( 39 ). They block the nucleus localization signal by binding to the RHD region of NF-κB, therefore preventing NF-κB from entering the nucleus to perform its function.…”

Relapse of psoriasis after cyclin‐dependent kinase 4 and 6 inhibitor: An emerging signalling pathway in cancer treatment and psoriasis

“…3 The effect of CDK4/6 inhibitors on the inflammatory cells, especially through STAT3 signalling, may be related to the role of IkappaB-Zeta (IκBζ). 4 IκBζ, encoded by the gene NFKBIZ (nuclear factor of kappa light polypeptide gene enhancer in B cells inhibitor, zeta), has been identified as a key regulator of transcription in associated genes. 5 IL-17A, alone or costimulated with TNF-α as well as IL-36 cytokines, triggers a NF-κBand STAT3-dependent transcriptional upregulation of IκBζ expression.…”

“…5 IL-17A, alone or costimulated with TNF-α as well as IL-36 cytokines, triggers a NF-κBand STAT3-dependent transcriptional upregulation of IκBζ expression. 4 Moreover, human psoriatic skin shows an upregulated expression of IκBζ. 4 CDK4/6-mediated phosphorylation of the methyltransferase EZH2 promotes STAT3 activation, triggering the subsequent methylation of STAT3 and induction of IκBζ expression in keratinocytes.…”

“…4 CDK4/6-mediated phosphorylation of the methyltransferase EZH2 promotes STAT3 activation, triggering the subsequent methylation of STAT3 and induction of IκBζ expression in keratinocytes. 4 CDK4/6 inhibitors therefore suppress the activity of STAT3, and has been proposed as a potential therapeutic target in topical application for psoriasis. 4 However, how this proinflammatory pathway actually influences psoriasis still needs to be further elucidated, since novel treatment as the biologics, especially TNF-α inhibitor, causes paradoxical reactions, and psoriasis flares following systemic glucocorticoid are well-known although topical steroid is a common first-line treatment.…”