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T helper 17 lineage differentiation is programmed by orphan nuclear receptors ROR alpha and ROR gamma.

ABSTRACT: T cell functional differentiation is mediated by lineage-specific transcription factors. T helper 17 (Th17) has been recently identified as a distinct Th lineage mediating tissue inflammation. Retinoic acid receptor-related orphan receptor gamma (ROR gamma) was shown to regulate Th17 differentiation; ROR gamma deficiency, however, did not completely abolish Th17 cytokine expression. Here, we report Th17 cells highly expressed another related nuclear receptor, ROR alpha, induced by transforming growth factor-beta and interleukin-6 (IL-6), which is dependent on signal transducer and activator of transcription 3. Overexpression of ROR alpha promoted Th17 differentiation, possibly through the conserved noncoding sequence 2 in Il17-Il17f locus. ROR alpha deficiency resulted in reduced IL-17 expression in vitro and in vivo. Furthermore, ROR alpha and ROR gamma coexpression synergistically led to greater Th17 differentiation. Double deficiencies in ROR alpha and ROR gamma globally impaired Th17 generation and completely protected mice against experimental autoimmune encephalomyelitis. Therefore, Th17 differentiation is directed by two lineage-specific nuclear receptors, ROR alpha and ROR gamma.

SUBMITTER: Yang XO

PROVIDER: S-EPMC2587175 | biostudies-literature | 2008 Jan

REPOSITORIES: biostudies-literature

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T helper 17 lineage differentiation is programmed by orphan nuclear receptors ROR alpha and ROR gamma.

Yang Xuexian O XO Pappu Bhanu P BP Nurieva Roza R Akimzhanov Askar A Kang Hong Soon HS Chung Yeonseok Y Ma Li L Shah Bhavin B Panopoulos Athanasia D AD Schluns Kimberly S KS Watowich Stephanie S SS Tian Qiang Q Jetten Anton M AM Dong Chen C

Immunity 20071227 1

T cell functional differentiation is mediated by lineage-specific transcription factors. T helper 17 (Th17) has been recently identified as a distinct Th lineage mediating tissue inflammation. Retinoic acid receptor-related orphan receptor gamma (ROR gamma) was shown to regulate Th17 differentiation; ROR gamma deficiency, however, did not completely abolish Th17 cytokine expression. Here, we report Th17 cells highly expressed another related nuclear receptor, ROR alpha, induced by transforming g ...[more]

PMID: 18164222

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Project description:ROR alpha1 and RVR are orphan members of the superfamily of nuclear hormone receptors which constitutively activate and repress, respectively, gene transcription by binding to a common DNA sequence. In an attempt to understand the physiological functions of these two transcription factors, we aimed to identify target genes. We have identified a consensus binding site for ROR alpha1 and RVR in the first intron of the N-myc gene that we designated N-myc RORE (ROR response element). Unlike most of the intronic sequence, the region encompassing the N-myc RORE is highly conserved between human and mouse, underscoring its importance. Our studies revealed that ROR alpha1 and RVR specifically bind to the human and mouse N-myc ROREs and transactivate and transrepress, respectively, reporter constructs containing the ROREs. Moreover, Northern blot analysis demonstrated a direct modulation of an exogenously introduced N-myc gene by ROR alpha1 and RVR in COS-1 cells. This effect is mediated through the N-myc RORE, since mutation of this site abolished the regulatory effects of both receptors. While transfection of ROR alpha1 in P19 embryonic carcinoma cells had no effect on the levels of endogenous N-myc mRNA, RVR down-regulated its expression. The regulatory function of the N-myc RORE was further demonstrated by the rat embryonic fibroblast (REF) transformation assay. Mutation of the RORE increased the oncogenic potential of the N-myc gene in the REF assay. The foci were more numerous and significantly larger with the mutated than with the wild-type N-myc gene, regardless of ROR alpha1 or RVR expression. Moreover, concomitant expression of ROR alpha1 and wild-type N-myc resulted in a twofold increase in the number of transformed foci. In contrast, RVR expression resulted in the formation of foci that could be established as permanent clones with a very low frequency compared to foci transformed in its absence. These observations show that ablation of the RORE results in a more oncogenic form of N-myc and suggest that deregulation of the activity of the ROR alpha1 and RVR could contribute to the initiation and progression of certain neoplasias.

Dataset Information

T helper 17 lineage differentiation is programmed by orphan nuclear receptors ROR alpha and ROR gamma.

Publications

T helper 17 lineage differentiation is programmed by orphan nuclear receptors ROR alpha and ROR gamma.

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