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IL-3,IL-5,and GM-CSF are related hematopoietic cytoines that are important for allergic inflammation. The receptors for human IL-5,IL-3,and GM-CSF are members of the hematopoietin receptor superfamily and are comprised of a cytokine-specific alpha chain and the common beta chain that is shared among these cytokines for signaling. Each of these cytokines contributes to the differentiation and function of leukocyte subpopulations and have clinical importance in protective immunity and in the pathophysiology of a spectrum of immunologic diseases that are as diverse as allergy and asthma,pulmonary alveolar proteinosis,neurodegenerative diseases,and malignancies. Delineating the biology of these cytokines is enabling the development of new strategies for diagnosing and treating these diseases and modulating immune responses. View Publication

UNLABELLED Basal-like breast cancer (BLBC) is an aggressive subtype of breast cancer which is often enriched with cancer stem cells (CSC),but the underlying molecular basis for this connection remains elusive. We hypothesized that BLBC cells are able to establish a niche permissive to the maintenance of CSCs and found that tumor cell-derived periostin (POSTN),a component of the extracellular matrix,as well as a corresponding cognate receptor,integrin $$(v)$$(3),are highly expressed in a subset of BLBC cell lines as well as in CSC-enriched populations. Furthermore,we demonstrated that an intact periostin-integrin $$3 signaling axis is required for the maintenance of breast CSCs. POSTN activates the ERK signaling pathway and regulates NF-$$B-mediated transcription of key cytokines,namely IL6 and IL8,which in turn control downstream activation of STAT3. In summary,these findings suggest that BLBC cells have an innate ability to establish a microenvironmental niche supportive of CSCs. IMPLICATIONS The findings reported here indicate that POSTN produced by CSCs acts to reinforce the stem cell state through the activation of integrin receptors and the production of key cytokines. View Publication

Chronic myelomonocytic leukemia (CMML) is a clinically heterogeneous neoplasm in which JAK2 inhibition has demonstrated reductions in inflammatory cytokines and promising clinical activity. We hypothesize that annotation of inflammatory cytokines may uncover mutation-independent cytokine subsets associated with novel CMML prognostic features. A Luminex cytokine profiling assay was utilized to profile cryopreserved peripheral blood plasma from 215 CMML cases from three academic centers,along with center-specific,age-matched plasma controls. Significant differences were observed between CMML patients and healthy controls in 23 out of 45 cytokines including increased cytokine levels in IL-8,IP-10,IL-1RA,TNF-alpha$,IL-6,MCP-1/CCL2,hepatocyte growth factor (HGF),M-CSF,VEGF,IL-4,and IL-2RA. Cytokine associations were identified with clinical and genetic features,and Euclidian cluster analysis identified three distinct cluster groups associated with important clinical and genetic features in CMML. CMML patients with decreased IL-10 expression had a poor overall survival when compared to CMML patients with elevated expression of IL-10 (P = 0.017),even when adjusted for ASXL1 mutation and other prognostic features. Incorporating IL-10 with the Mayo Molecular Model statistically improved the prognostic ability of the model. These established cytokines,such as IL-10,as prognostically relevant and represent the first comprehensive study exploring the clinical implications of the CMML inflammatory state. View Publication

The differentiation of effector CD8(+) T cells is a dynamically regulated process that varies during different infections and is influenced by the inflammatory milieu of the host. In this study,we define three signals regulating CD8(+) T cell responses during tuberculosis by focusing on cytokines known to affect disease outcome: IL-12,type I IFN,and IL-27. Using mixed bone marrow chimeras,we compared wild-type and cytokine receptor knockout CD8(+) T cells within the same mouse following aerosol infection with Mycobacterium tuberculosis. Four weeks postinfection,IL-12,type 1 IFN,and IL-27 were all required for efficient CD8(+) T cell expansion in the lungs. We next determined if these cytokines directly promote CD8(+) T cell priming or are required only for expansion in the lungs. Using retrogenic CD8(+) T cells specific for the M. tuberculosis Ag TB10.4 (EsxH),we observed that IL-12 is the dominant cytokine driving both CD8(+) T cell priming in the lymph node and expansion in the lungs; however,type I IFN and IL-27 have nonredundant roles supporting pulmonary CD8(+) T cell expansion. Thus,IL-12 is a major signal promoting priming in the lymph node,but a multitude of inflammatory signals converge in the lung to promote continued expansion. Furthermore,these cytokines regulate the differentiation and function of CD8(+) T cells during tuberculosis. These data demonstrate distinct and overlapping roles for each of the cytokines examined and underscore the complexity of CD8(+) T cell regulation during tuberculosis. View Publication

A hallmark of pancreatic ductal adenocarcinoma (PDAC) is an exuberant stroma comprised of diverse cell types that enable or suppress tumor progression. Here,we explored the role of oncogenic KRAS in protumorigenic signaling interactions between cancer cells and host cells. We show that KRAS mutation (KRAS) drives cell-autonomous expression of type I cytokine receptor complexes (IL2r?–IL4r? and IL2r?–IL13r?1) in cancer cells that in turn are capable of receiving cytokine growth signals (IL4 or IL13) provided by invading Th2 cells in the microenvironment. Early neoplastic lesions show close proximity of cancer cells harboring KRAS and Th2 cells producing IL4 and IL13. Activated IL2r?–IL4r? and IL2r?–IL13r?1 receptors signal primarily via JAK1-STAT6. Integrated transcriptomic,chromatin occupancy,and metabolomic studies identified MYC as a direct target of activated STAT6 and that MYC drives glycolysis. Thus,paracrine signaling in the tumor microenvironment plays a key role in the KRAS-driven metabolic reprogramming of PDAC. SIGNIFICANCE: Type II cytokines,secreted by Th2 cells in the tumor microenvironment,can stimulate cancer cell-intrinsic MYC transcriptional upregulation to drive glycolysis. This KRAS-driven heterotypic signaling circuit in the early and advanced tumor microenvironment enables cooperative protumorigenic interactions,providing candidate therapeutic targets in the KRAS pathway for this intractable disease. View Publication