The STAT3 isoforms α and β have unique and specific functions

Abstract

Signal transducer and activator of transcription 3 (STAT3) is the main mediator of interleukin 6 (IL-6)-type cytokine signaling. It exists in two isoforms: the full-length STAT3 alpha and the truncated STAT3 beta, generally thought to act as a dominant negative factor. To assess their relative functions, we ablated the expression of either isoform by gene targeting. We show here that in vivo STAT3 beta is not a dominant negative factor. Its expression can rescue the embryonic lethality of a STAT3-null mutation and it can by itself induce the expression of specific STAT3 target genes. Nevertheless, STAT3 alpha has nonredundant roles such as modulation of cellular responses to IL-6 and mediation of IL-10 function in macrophages.

Mechanism of Interferon-gamma mediated down-regulation of Interleukin-10 gene expression

“…The role of Stat3 in IL-10 gene expression was, however, confirmed in other cell lines and in knock-out mice (Herbeuval et al, 2004) (Cheng et al, 2003) (Maritano et al, 2004). Recently it was shown that SOCS3 deficiency in murine TCR-stimulated T cells led to increased Stat3 activity and IL-10 expression (Kinjyo et al, 2006).…”

IFN Regulatory Factor-2 Regulates Macrophage Apoptosis through a STAT1/3- and Caspase-1-Dependent Mechanism

“…Although STAT3␤ was originally considered to be a negative regulator of transcription (16), it was later shown that the STAT3 isoforms ␣ and ␤ have unique and specific functions (18). Both seem to be necessary for the correct balance of immune responses, because the specific ablation of STAT3␤ impairs recovery from endotoxin shock and affects STAT3-dependent gene expression (61,62).…”

“…Total RNA was isolated from liver samples, and 20 g of RNA was converted to cDNA with StrataScript reverse transcriptase (FairPlay Microarray Labeling Kit; Stratagene), using oligo(dT) [12][13][14][15][16][17][18] as a primer. cDNA was purified and labeled with Cy3 and Cy5 (Amersham Biosciences).…”

“…The ratio of the STAT3 isoforms appears to be related to the stage of cellular differentiation. STAT3␣ is more prevalent during early stages of granulocytic differentiation, whereas STAT3␤ is present later during maturation (17,18). Little is known about the function of STAT3␥.…”

STAT5 isoforms: controversies and clarifications

“…These mice exhibited an altered pattern of STAT3-responsive gene expression, suggesting a role for the STAT3β isoform in controlling systemic inflammation [12]. Similarly, other work has argued that the STAT3β isoform is not a true dominant-negative factor, as it retains the ability to activate a number of STAT3 target genes [13]. The STAT4β isoform has also been shown to induce many IL-12 (interleukin 12)-responsive genes in common with STAT4α, in addition to a unique subset of genes [14].…”