Review
Ups and downs: The STAT1:STAT3 seesaw of Interferon and gp130 receptor signalling

https://doi.org/10.1016/j.semcdb.2008.06.004Get rights and content

Abstract

Downstream of cytokine or growth factor receptors, STAT3 counteracts inflammation and promotes cell survival/proliferation and immune tolerance while STAT1 inhibits proliferation and favours innate and adaptive immune responses. STAT1 and STAT3 activation are reciprocally regulated and perturbation in their balanced expression or phosphorylation levels may re-direct cytokine/growth factor signals from proliferative to apoptotic, or from inflammatory to anti-inflammatory. Here we review the functional canonical and non-canonical effects of STAT1/3 activation and discuss the hypothesis that perturbation of their expression and/or activation levels may provide novel therapeutic strategies in different clinical settings and particularly in cancer.

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).

References (172)

  • R.M. Strieter et al.

    Interferon gamma-inducible protein 10 (IP-10), a member of the C-X-C chemokine family, is an inhibitor of angiogenesis

    Biochem Biophys Res Commun

    (1995)
  • S. Li et al.

    Candidate genes associated with tumor regression mediated by intratumoral IL-12 electroporation gene therapy

    Mol Ther

    (2004)
  • M. Chatterjee-Kishore et al.

    Different requirements for signal transducer and activator of transcription 1alpha and interferon regulatory factor 1 in the regulation of low molecular mass polypeptide 2 and transporter associated with antigen processing 1 gene expression

    J Biol Chem

    (1998)
  • A. Muhlethaler-Mottet et al.

    Activation of the MHC class II transactivator CIITA by interferon-gamma requires cooperative interaction between Stat1 and USF-1

    Immunity

    (1998)
  • S. Ito et al.

    Interleukin-10 inhibits expression of both interferon alpha- and interferon gamma- induced genes by suppressing tyrosine phosphorylation of STAT1

    Blood

    (1999)
  • J.K. Riley et al.

    Interleukin-10 receptor signaling through the JAK-STAT pathway, requirement for two distinct receptor-derived signals for anti-inflammatory action

    J Biol Chem

    (1999)
  • K. Takeda et al.

    Enhanced Th1 activity and development of chronic enterocolitis in mice devoid of Stat3 in macrophages and neutrophils

    Immunity

    (1999)
  • I. Arany et al.

    Differentiation-dependent expression of signal transducers and activators of transcription (STATs) might modify responses to growth factors in the cancers of the head and neck

    Cancer Lett

    (2003)
  • Y. Qing et al.

    Alternative activation of STAT1 and STAT3 in response to interferon-gamma

    J Biol Chem

    (2004)
  • S.P. Barry et al.

    Role of the JAK-STAT pathway in myocardial injury

    Trends Mol Med

    (2007)
  • D. Hilfiker-Kleiner et al.

    Many good reasons to have STAT3 in the heart

    Pharmacol Ther

    (2005)
  • D. Hilfiker-Kleiner et al.

    A cathepsin D-cleaved 16 kDa form of prolactin mediates postpartum cardiomyopathy

    Cell

    (2007)
  • A. Stephanou et al.

    Ischemia-induced STAT-1 expression and activation play a critical role in cardiomyocyte apoptosis

    J Biol Chem

    (2000)
  • D.M. Walters et al.

    Susceptibility of signal transducer and activator of transcription-1-deficient mice to pulmonary fibrogenesis

    Am J Pathol

    (2005)
  • W. Li et al.

    High-dose cellular IL-10 exacerbates rejection and reverses effects of cyclosporine and tacrolimus in Mouse cardiac transplantation

    Transplant Proc

    (1997)
  • R.W. Rose et al.

    Altered levels of STAT1 and STAT3 influence the neuronal response to interferon gamma

    J Neuroimmunol

    (2007)
  • M.P. Gil et al.

    Modulation of STAT1 protein levels: a mechanism shaping CD8 T-cell responses in vivo

    Blood

    (2006)
  • X.P. Chen et al.

    SOCS proteins, regulators of intracellular signaling

    Immunity

    (2000)
  • J.C. Marine et al.

    SOCS1 deficiency causes a lymphocyte-dependent perinatal lethality

    Cell

    (1999)
  • W.S. Alexander et al.

    SOCS1 is a critical inhibitor of interferon gamma signaling and prevents the potentially fatal neonatal actions of this cytokine

    Cell

    (1999)
  • S. Ilangumaran et al.

    Regulation of the immune system by SOCS family adaptor proteins

    Semin Immunol

    (2004)
  • S. Wormald et al.

    The comparative roles of suppressor of cytokine signaling-1 and -3 in the inhibition and desensitization of cytokine signaling

    J Biol Chem

    (2006)
  • H.H. Ho et al.

    Role of STAT3 in type I interferon responses, negative regulation of STAT1-dependent inflammatory gene activation.

    J Biol Chem

    (2006)
  • L. Thyrell et al.

    Interferon alpha induces cell death through interference with interleukin 6 signaling and inhibition of STAT3 activity.

    Exp Cell Res

    (2007)
  • H.S. Kim et al.

    STAT1 as a key modulator of cell death

    Cell Signal

    (2007)
  • M. Huang et al.

    Constitutive activation of stat 3 oncogene product in human ovarian carcinoma cells

    Gynecol Oncol

    (2000)
  • A. Horiguchi et al.

    Activation of signal transducer and activator of transcription 3 in renal cell carcinoma: a study of incidence and its association with pathological features and clinical outcome

    J Urol

    (2002)
  • F.M. Corvinus et al.

    Persistent STAT3 activation in colon cancer is associated with enhanced cell proliferation and tumor growth

    Neoplasia (New York, NY)

    (2005)
  • D.E. Levy et al.

    Stats: transcriptional control and biological impact

    Nat Rev Mol Cell Biol

    (2002)
  • G.R. Stark et al.

    How cells respond to interferons

    Ann Rev Biochem

    (1998)
  • C. Schindler et al.

    Interferons as a paradigm for cytokine signal transduction

    Cell Mol Life Sci

    (1999)
  • V. Poli et al.

    STAT3 function in vivo

  • L.C. Platanias

    Mechanisms of type-I- and type-II-interferon-mediated signalling

    Nat Rev

    (2005)
  • P.C. Heinrich et al.

    Interleukin-6-type cytokine signalling through the gp130/Jak/STAT pathway.

    Biochem J

    (1998)
  • S.J. Baker et al.

    Hematopoietic cytokine receptor signaling

    Oncogene

    (2007)
  • C. Sachsenmaier et al.

    STAT activation by the PDGF receptor requires juxtamembrane phosphorylation sites but not Src tyrosine kinase activation

    Oncogene

    (1999)
  • K. Schroder et al.

    Interferon-gamma: an overview of signals, mechanisms and functions

    J Leukoc Biol

    (2004)
  • P. Bernabei et al.

    Interferon-gamma receptor 2 expression as the deciding factor in human T, B, and myeloid cell proliferation or death

    J Leukoc Biol

    (2001)
  • Y. Miura et al.

    TRAIL expression up-regulated by interferon-gamma via phosphorylation of STAT1 induces myeloma cell death

    Anticancer Res

    (2006)
  • E.A. Choi et al.

    Stat1-dependent induction of tumor necrosis factor-related apoptosis-inducing ligand and the cell-surface death signaling pathway by interferon beta in human cancer cells

    Cancer Res

    (2003)
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    The first two authors equally contributed to this work.

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