Transcript How is the STAT3 pathway activated?

STAT3 and the Immune System
Maureen Sherry Lynes
February 29, 2012
Overview
 STAT family; STAT3 signaling and structure
 Role of STAT3 revealed by tissue specific knockouts
 STAT3 and the anti-tumor immune response
Therapeutic approaches for targeting STAT3
Paper discussion
The STAT Family of Transcription Factors
 7 mammalian STAT proteins
 latent cytoplasmic transcription factors
 Important in a wide range of physiological processes
STAT1
STAT2
STAT3
STAT4
STAT5A
STAT5B
STAT6
Impaired interferon response; increased susceptibility to tumors
Impaired interferon response
Embryonic lethal
Impaired Th1 differentiation due to loss of Il-12 responsiveness
Impaired mammary gland development (decreased prolactin response)
Impaired growth (growth hormone signaling impaired)
Impaired Th1 differentiation due to loss of Il-4 responsiveness
Adapted from Darnell and Levy, 2002
How is the STAT3 pathway activated?
•Cytokines, growth factors
•Secreted by diverse cell
types in response to
diverse processes
•Receptor specific
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Minegishi et al 2011
The STAT3 Signaling Pathway
Negative Regulation of
STAT3 signaling
1.
Cytoplasmic
phosphatases
2.
SOCs proteins
3.
Pias Proteins
4.
STAT3ß
Domain Structure of STAT3
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Figure 1.2. Domain structure of the STAT proteins.
STAT3 Target Genes
Growth (C-myc, cyclin D)
Apoptosis (Survivin, bcl-xl)
STAT3
Differentiation
Angiogenesis (VEGF)
Immortalization (hTERT)
Tissue Specific STAT3 Knockouts
•Brain: obesity, inability to control
temperature, diabetes
•Skin: impaired wound healing, resistance
to skin cancer
•Mouse Embryonic Stem Cells: loss of
pluripotency
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•Lung
•Macrophages and Neutrophils
•Liver
•Th17 development
Gao et al, 2004.
STAT3 and the Acute Phase Response
•Liver: site of integration of signals from tissue, toxins and bacterial products in blood,
etc
• Macrophages in the periphery: cytokine release
•Hepatocytes respond to cytokines (IL-6, IL-1 for example) and upregulate appropriate
response proteins (clotting, innate responses to bacterial infection, toxins, etc)
•Hepatocyte deletion of STAT3- polymicrobial sepsis
LPS injection or cecal
ligation and puncture:
Sakamori et al 2007
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Similar bacterial load;
decreased acute phase
proteins, increased
inflammatory cytokines
such as IL-6 and TNFa
STAT3 in macrophages and neutrophils
•STAT3 deleted in cells expressing lysozyme M
•Mice were susceptible to LPS-induced endotoxic shock
•Macrophages constitutively activated
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Takeda et al, 1999.
STAT3 in macrophages and neutrophils
•STAT3 -/- macrophages are resistant to IL-10
•IL-10 normally dampens macrophage activation and response
•LysmCre STAT3 mice develop chronic enterocholitis
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STAT3 in the lung epithelium
• House dustmite extract: induces allergic inflammation in the lung, as well
as STAT3 activation
•Lung specific STAT3 KO: appears normal
•STAT3 lung KO: decreased airway hyperresponsiveness, immune
infiltration upon HDM challenge
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Simeone et al, 2007.
STAT3 in Th17 Differentiation
•CD4+, defense against extracellular
bacteria, fungi
•Pathogenic autoimmune responses
•Celiac, IBD, etc
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Fischer 2008
STAT3 in hyper IgE syndrome
activation
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DNA
binding
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STAT3 in hyper IgE syndrome
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Recurrent skin and lung
infections (Th17, lung
epithelial defects?)
Activation, Duration, and extent of STAT3 signaling
is tightly regulated
•Brain: obsesity, inability to control
temperature, diabetes
•Skin: impaired wound healing, resistance
to skin cancer
•Mouse Embryonic Stem Cells: loss of
pluripotency
•Lung- promotes allergic inflammation
•Macrophages and Neutrophilsprevents constitutve activation,
•Liver: actue phase response;
integration of signals from tissues
•Th17 differentiation
Gao et al, 2004.
STAT3 and tumorigenesis
STAT3 is constitutively activated in many human cancers
 Inappropriately activated or overexpressed
 Prevents apoptosis, stimulates migration, stimulates proliferation, increases
angiogenesis
Upregulates cytokines that perpetuate STAT3 activation in the tumor and
surrounding tissue
Wang, Rich et al. Stem Cells 2009
DN STAT3 induces melanoma regression in a mouse model
Transfection of B16 tumors with dominant negative STAT3 induces tumor
regression
 Bystander effect: regression disproportionate to transfection
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Niu et al Cancer Research 1999
STAT3 Suppresses Anti-Tumor Immunity
Cultured B16 cells transfected with DN STAT3: increased production of proinflammatory cytokines and chemokines (TNFa, RANTES, IP-10)
 In vivo: enhances macrophage and neutrophil infiltration
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Wang et al Nature Med 2004
STAT3 Suppresses Anti-Tumor Immunity
Yu et al Nature Reviews 2007
STAT3 as a therapeutic target
STAT3 as a therapeutic target
Activation
EGFR antibodies; small molecules
Jak inhibitors
Multi-receptor kinase inhibitors
Protein-protein interactions
Small molecules to prevent dimerization
phosphoTyr peptides
DNA binding
Double stranded oligonucleotides
Nuclear translocation, natural inhibitors
Summary
STAT3 is a cytokine and growth factor activated transcription factor
 STAT3 has a wide range of functions, both anti and pro inflammatory
depending on the tissue and physiological context
STAT3 is also involved in disease states, such as asthma, colitis, and
cancer
STAT3 can suppress anti-tumor immunity
STAT3 directed therapeutics is an active area of research
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