ReviewUps and downs: The STAT1:STAT3 seesaw of Interferon and gp130 receptor signalling
Section snippets
Differential STAT1 and STAT3 activation by interferons or gp130 cytokines
Cytokines and growth factors play a major role in regulating responses to inflammation or immune challenge and in mediating cellular decisions during development and neoplastic growth. Cytokine receptors lack enzymatic activity but are associated with cytoplasmic tyrosine kinases belonging to the JAK family (recently reviewed in ref. [1]). Ligand stimulation triggers receptor dimerization and activation of the associated JAKs, leading to receptor tyrosine phosphorylation followed by recruitment
Opposing roles of STAT1 and STAT3 in regulating survival/proliferation
The crucial decision between cell survival or apoptosis is at the basis of fundamental physiological and pathological processes such as development and tumor growth, and is often the result of a fine balance between cytokines and growth factors with opposing functions. Disruption of this equilibrium may result in uncontrolled growth and tumor development. In most cell types, STAT1 and STAT3 play opposite roles in directing cells towards proliferation or apoptotic cell death.
The IFNγ/STAT1
Opposing roles of STAT1 and STAT3 in inflammation
The inflammatory response is under tight control by both positive and negative signals, finely orchestrated by different pro- and anti-inflammatory cytokines and mediators. Loss of this balance leads to pathological conditions such as defective immune response or chronic inflammation. In addition, an important correlation between inflammation and cancer exists in that the intensity and duration of inflammatory responses influences the development of a favourable micro-environment for neoplastic
The balance between STAT1 and STAT3 may determine the outcome of cytokine treatment and drive healing or pathological responses
Despite the fact that STAT1 and STAT3 can play opposing roles in cell proliferation, apoptotic death or inflammation, they share many activating stimuli. In addition, STAT1:STAT3 cross-regulation and their relative abundance and activation levels appear to play a fundamental role in directing cellular responses to different combinations of cytokines [34], [56], [57]. Indeed, several studies on STAT-deficient cells have revealed the existence of reciprocal STAT1:STAT3 regulatory mechanisms [58],
Physiological mechanisms of STAT1:STAT3 cross-regulation
Although the first indications of the importance of a balanced expression/activation of STAT1 and STAT3 came from studies on genetically modified STAT-deficient cells [58], [60], several observations suggest that modulation of their levels can play a role in cytokine signalling and function also in more physiological contexts. Cells are normally exposed to a complex cytokine milieu, and cytokine-induced alterations in STATs levels resulting in their differential activation may represent a
Role of STAT1, STAT3 and their balance in tumorigenesis
STAT1 plays a critical role in tumorigenesis by exerting a complex array of activities and functions on both tumor cells and the immune system and is usually considered as a tumor suppressor [93]. In contrast, STAT3 is considered as an oncogene and its constitutive activation is reported in nearly 70% of solid and hematological tumors [94], [95], [96], [97], [98], [99], [100]. Moreover, the over-expression of a constitutively active form, STAT3C, is sufficient to transform fibroblasts and other
Conclusions
Many studies are underway to develop inhibitors of STAT3, mainly aiming at exerting anti-tumor effects [167]. These studies are still at an early stage as the safety and efficacy of these compounds have not been clinically evaluated yet. However, as described in the above sections, alterations of the balanced expression and/or activation of STAT1 and STAT3 may lead to unexpected results, since the targeted cells act in a micro-environmental context where different stimuli can influence their
Acknowledgements
We wish to thank Drs. F. Bazzoni for discussions inspiring this work and I. Barbieri for sharing his unpublished results. Work in the author's laboratories was supported by the Italian Ministry of Research (MIUR PRIN) and by the Italian Association for Cancer Research (AIRC). G. Regis was the recipient of a “Young Researchers Contract” supported by FIRB (Fondo per gli Investimenti della Ricerca di Base).
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The first two authors equally contributed to this work.