Page 219 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 16 Cytokine/Receptor Families and Signal Transduction 171

enforced expression of a constitutively active STAT3 homodimer is STAT5
sufficient to transform immortalized fibroblasts. STAT3 inhibitors are
in early clinical trials for advanced malignancies. The genes encoding STAT5A and STAT5B are juxtaposed, and the
transcriptional start sites are within 10 kb of each other. Although
Stat5a and Stat5b gene promoters might share certain regulatory
STAT4 elements, lineage specific expressions have been reported. The highly
related STAT5 proteins (A and B) are activated in response to a
STAT4 is predominantly activated in response to IL-12, which drives variety of cytokines and tyrosine kinase receptors. Mice lacking
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T-helper cell differentiation towards the Th1 and Th17 pathways. STAT5A, STATB, or STAT5A/B, display distinct phenotypes
The phenotype of STAT4-deficient mice is very similar to that of suggesting discrete functions for these proteins. STAT5A deficiency
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mice lacking IL-12. IL-12 promotes differentiation of naive CD4 T results in the loss of PRL-dependent mammary gland development,
cells to Th1 cells, which produce IFN-γ and augment cell-mediated which is necessary for lactation. STAT5B-deficient mice are sexually
immune responses. Th1 cells are critical in host defense against dimorphic with growth retardation. In contrast, a good portion
intracellular pathogens and tumors and in the pathogenesis of auto- of STAT5A/B double knockout mice die within a few weeks of
immune diseases. Thus the phenotype of STAT4-deficient mice birth, are infertile with defective corpus luteum development, and
includes impaired Th1 differentiation, IFN-γ production, and cell- have defective mammary gland development. Both male and female
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mediated immunity. IL-12-, IL-12 receptor-, and STAT4-deficient STAT5A/B-deficient mice are small with smaller fat pads and reduced
mice have increased susceptibility to infection with intracellular levels of insulin-like growth factor-1 (IGF-1). STAT5A/B double
organisms. STAT4-deficient mice are resistant to autoimmune dis- knockout mice have hypocellular bone marrows, lymphopenia,
eases characterized by a Th1 response. A common haplotype of neutrophilia, and modest anemia and thrombocytopenia. Moreover,
STAT4 gene has been shown to be associated with susceptibility to the hematopoietic progenitors of STAT5A/B-deficient have defec-
rheumatoid arthritis, systemic lupus erythematosis, and primary tive bone marrow repopulating potential. Myeloid development is
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Sjögren syndrome. In acute sepsis, STAT4 deficiency is associated grossly normal in STAT5A/B knockout mice, but in vitro cytokine
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with improved survival, whereas STAT4 mice had increased lethal- dependent proliferation, survival, and migration of myeloid cells are
ity in a noninfectious sepsis model. It appears that STAT4 may have impaired. With respect to T- and B-cell development, complete dele-
either proinflammatory or antiinflammatory effects, depending upon tion of the STAT5A/B locus results in severely impaired lymphoid
context. development and differentiation with abrogated T-cell receptor γ
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STAT4 is also activated by IL-23. In addition, in humans, but not rearrangement and survival of peripheral CD8 T. In other words,
in mice, IFN-α/β induces STAT4 phosphorylation. This is notable complete STAT5 deficiency results in SCID, similar in lymphoid
because IFN-α/β can promote Th1 differentiation in humans and phenotype to deficiencies of IL-7R, γc, and JAK3. Deficiency of both
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not in mice. This has been attributed to STAT4/STAT2 dimer being STAT5A and STAT5B results in loss of CD4 regulatory T (Treg)
recruited to the human type I IFN receptor via the carboxy terminus cells that express the transcription factor Foxp3, whereas constitutive
of STAT2. STAT4 also mediates IFN-γ production by dendritic cells activation of STAT5B enforces Foxp3-positive Treg cell development,
and macrophages induced by IL-12, which may explain the mecha- bypassing the requirements for upstream cytokine or costimulatory
nisms by which dendritic cells (DC) promote Th1 differentiation. signals to activate Foxp3 transcription. STAT5 deficiency abrogates
transformation by Tel-JAK but not by v-Abl or BCR-abl. Mutations
in the Stat5b gene has been documented in a few patients with severe
STAT6 growth retardation. Loss of functional STAT5B is associated with
severe IGF-1 deficiency, indicating that this pathway is responsible
STAT6 is primarily activated by IL-4 and IL-13. STAT6-deficient for most of the GH-induced IGF-1 production.
mice lack most of the physiologic functions associated with IL-4, in
particular the ability of IL-4 to induce the in vitro differentiation of
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Th2 cells. STAT6 is critically involved in several distinct aspects of Negative Regulators of Cytokine Signaling
allergic inflammatory disease, like airway hyperresponsiveness,
eosinophilic infiltration, and responses of mast cells. B cells of Whereas the JAK-STAT pathway activation is important for homeo-
STAT6-deficient mice cannot undergo class switching to produce IgE stasis, its inactivation prevents excessive responses to cytokine stimu-
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against helminthes and allergens. As expected, STAT6 mice have lation. In addition to protein tyrosine phosphatases (PTPs), other
impaired expulsion of helminthic parasites and reduced pathology in factors are involved in downregulating this pathway as discussed later.
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models of asthma. STAT6 mice have increased lethality, inflamma-
tion, and cytokine production in a noninfection induced model of
endotoxemia, but reduced lethality and enhanced clearance of bacte- Src-Homology 2 Containing Phosphatase 1
ria in an infection model. (PTPN6)
STAT6 induces expression of GATA3, which is considered the
Th2 cell master regulator. Transgenic mice expressing IL-4 or consti- The expression of SHP-1, a cytoplasmic phosphotyrosine phospha-
tutively active STAT6 are characterized by the development of tase is limited to the hematopoietic system. SHP-1 was identified as
spontaneous allergic inflammation. Certain chemokines such as the protein encoded by the mutated locus (Hcph) in the moth-eaten
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CCL11, CCL17 CCL22, and CCL26 have been reported to be regu- (me) mice. These mice that are characterized by reduced SHP-1
lated in a STAT6-dependent manner and are involved in allergic display severe immunologic dysfunction; enhanced proliferation of
disorders. Although a number of pathways, including the mitogen- macrophages and neutrophils in the lungs, which leads to pneumo-
activated protein kinase and the phosphoinositide-3-kinase pathways, nitis; and patchy dermatitis that results in the “moth-eaten” pheno-
are involved in signal transduction because of IL-4, IL-4–induced T type. SHP-1 associates with cytokine receptors and dephosphorylates
cell differentiation appears to occur almost exclusively via STAT6. JAK kinases. For example, it downregulates EPO-induced signaling
IL-4 also antagonizes Th1 responses through STAT6. In fact, residual by binding to the EPOR and dephosphorylating JAK2 associated
STAT4-independent Th1 differentiation becomes apparent in doubly with it. SHP-1 also dephosphorylates JAK1, because IFN-α–induced
deficient STAT4/STAT6 knockout mice. A study of murine mast phosphorylation of JAK1 is enhanced in SHP-1–deficient macro-
cells demonstrated IL-15–inducible STAT6 phosphorylation, involv- phages. SHP-1 also interacts with JAK3. This interaction may explain
ing Tyk2, although IL-15 was less potent than IL-4. 27 the activation of JAK3/STAT3 pathway in some cases of ALK (+)
Functional deletion of STAT4 or STAT6 led to the determination anaplastic large cell lymphoma where SHP-1 appears to be suppressed
that Th1 cells regulate hematopoietic progenitor cell homeostasis by promoter methylation. The expression of an inactive SHP-1 in
mediated by the production of oncostatin M. 28 the cytokine-dependent cell line Ba/F3 increased the proliferative