Download 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
QuickTime™ and a
decompressor
are needed to see this picture.
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
Q uickTim e™ and a
decom pr essor
ar e needed t o see t his pict ur e.
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
QuickTime™ and a
decompressor
are needed to see this picture.
•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
QuickTime™ and a
decompressor
are needed to see this picture.
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
QuickTime™ and a
decompressor
are needed to see this picture.
QuickTime™ and a
decompressor
are needed to see this picture.
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
QuickTime™ and a
decompressor
are needed to see this picture.
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
QuickTime™ and a
decompressor
are needed to see this picture.
Simeone et al, 2007.
STAT3 in Th17 Differentiation
•CD4+, defense against extracellular
bacteria, fungi
•Pathogenic autoimmune responses
•Celiac, IBD, etc
QuickTime™ and a
decompressor
are needed to see this picture.
Fischer 2008
STAT3 in hyper IgE syndrome
activation
QuickTime™ and a
decompressor
are needed to see this picture.
DNA
binding
QuickTime™ and a
decompressor
are needed to see this picture.
STAT3 in hyper IgE syndrome
QuickTime™ and a
decompressor
are needed to see this picture.
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
QuickTime™ and a
decompressor
are needed to see this picture.
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
QuickTime™ and a
decompressor
are needed to see this picture.
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
QuickTime™ and a
decompressor
are needed to see this picture.