Cytokines: Coordinators of Immune and Inflammatory Responses

Arai, Kohei; Lee, Frank; Miyajima, Atsushi; Miyatake, Shoichiro; Arai, Naoko; Yokota, Takashi

doi:10.1146/annurev.bi.59.070190.004031

Cited by 1,220 publications

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“…Activating signals ultimately result in cellular proliferation, and transcriptional induction and secretion of a number of cytokines including IL-2 (interleukin-2), IL-3, IFNg (interferon-gamma) and GM ± CSF (granulocytemacrophage colony-stimulating factor) (Stanley et al, 1985;Miyajima et al, 1988;Arai et al, 1990). These cytokines direct the e ector functions of various cell types involved in an immune response, including B cells, macrophages, mast cells, eosinophils and neutrophils.…”

Section: Introductionmentioning

confidence: 99%

ETS1, NFκB and AP1 synergistically transactivate the human GM – CSF promoter

et al. 1997

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Activation of helper T cells results in coordinate expression of a number of cytokines involved in di erentiation, proliferation and activation of the haematopoietic system. Granulocyte-macrophage colony stimulating factor (GM ± CSF) is one such cytokine, whose increased expression results mostly from increases in transcription. Cis-acting elements with NFkB, AP1 and ETS-like binding motifs have been identi®ed in the promoter region of the GM ± CSF gene, and are important or essential for transcriptional activity following T cell activation. ETS1 is a transcription factor of the ETS family that is expressed in T cells. We have previously shown that ETS1 can transactivate GM ± CSF in Jurkat T cells, but only after the cells have been stimulated by treatment with PMA and ionomycin, agents that mimic T cell activation. Thus we proposed that ETS1, which is expressed constitutively in Jurkat cells, may act in concert with PMA/ionomycin inducible factors. Here we show that ETS1 can transactivate a GM ± CSF reporter construct in unstimulated Jurkat cells, providing that either NFkB or AP1 transcription factors are supplied by co-transfection. We con®rm that binding of endogenous NFkB and AP1 is induced following PMA/ionomycin treatment of T cells. Transactivation by ETS1, NFkB and AP1 is synergistic, and mutation of the individual binding sites reveals that the transcriptional activities of these factors are interdependent. Our results suggest that constitutive ETS1, and inducible NFkB and AP1, cooperate as part of a higher order transcriptional complex in activated T cells.

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Section: Introductionmentioning

confidence: 99%

ETS1, NFκB and AP1 synergistically transactivate the human GM – CSF promoter

et al. 1997

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“…Populations of hematopoietic cells are precisely regulated through interactions with supporting cells as well as by the action of numerous humoral factors, i.e., hematopoietic cytokines (Arai et al, 1990). The lifespans of mature hematopoietic cells are generally short, and the proliferation and di erentiation of hematopoietic stem cells constantly replenish the cell population that has been lost from the periphery.…”

Section: Introductionmentioning

confidence: 99%

“…In contrast, a rapid expansion of a particular population occurs during in¯ammatory and immunological responses. Such inductive hematopoiesis is mainly controlled by activated T cells through the production of cytokines (Arai et al, 1990). When the in¯ammatory or immunological response is terminated, expanded cells are quickly eliminated and the hematopoietic system returns to the basal steady-state level.…”

Section: Introductionmentioning

confidence: 99%

Raf/MAPK and rapamycin-sensitive pathways mediate the anti-apoptotic function of p21Ras in IL-3-dependent hematopoietic cells

et al. 1997

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“…In many circumstances, this is achieved through interplay between distinct classes of cytokines that promote either cooperative or antagonistic effects (1)(2)(3). The T helper cell type I (Th1) 1 -derived cytokine IFN␥ promotes the development of cell-mediated immunity (3)(4)(5)(6) and often functions cooperatively with TNF to regulate pro-inflammatory gene expression in a variety of cell types (7,8).…”

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Interleukin-4/STAT6 Represses STAT1 and NF-κB-dependent Transcription through Distinct Mechanisms

Ohmori

Hamilton

2000

Journal of Biological Chemistry

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Cytokines mediate much of the cell to cell communication that is necessary for control of immune-mediated inflammation. In many circumstances, this is achieved through interplay between distinct classes of cytokines that promote either cooperative or antagonistic effects (1-3). The T helper cell type I (Th1) 1 -derived cytokine IFN␥ promotes the development of cell-mediated immunity (3-6) and often functions cooperatively with TNF to regulate pro-inflammatory gene expression in a variety of cell types (7,8). In contrast, the Th2-derived cytokine IL-4 promotes humoral immunity and differentiation of Th2 cells (1,3,5,6,9) in part via antagonistic effects on Th1-cytokine-driven gene expression (3, 5, 10 -12).Intracellular signaling events linked with response to cytokine-receptor interaction have been extensively studied. Signal transducers and activators of transcription (STATs) are latent cytoplasmic transcription factors that are phosphorylated at a single tyrosine residue via members of the Jak kinase family following ligand-receptor interaction, assemble in dimeric form, translocate to the nucleus, and bind to specific DNA sequence motifs (13-15). Prototypically, IFN␥ activates STAT1 homodimers that bind to IFN␥ activation sequences (GAS) composed of two inverted repeats separated by three intervening nucleotides (N3 site, TTCnnnGAA) and promote transcription of IFN␥-responsive genes (14, 16). Likewise, IL-4 leads to activation of STAT6 (17-19), which can stimulate gene transcription by binding to a sequence that resembles the GAS motif but instead contains four intervening nucleotides between the inverted repeat (N4 site, TTCnnnnGAA) (20 -24). Interestingly, STAT6 can also bind N3 GAS elements but with little or no transactivation potential (23,25,26).Although the negative regulatory role of IL-4 in immune inflammatory reactions has been well delineated (3, 5, 10 -12, 27-34), the molecular mechanisms involved remain incompletely understood. We have previously demonstrated that IL-4 does not inhibit tyrosine phosphorylation, nuclear translocation, nor DNA binding activity of STAT1 and that STAT6 is required for inhibition of IFN␥-inducible gene transcription in mouse macrophages (26,35). Because the cis-elements required for IFN␥-induced transcription (ISRE, GAS, and ␥RE) are also sufficient for IL-4-mediated inhibition and because STAT6 homodimers are capable of binding to these sites without transactivating function (26,35,36), it has been suggested that inhibition might involve competition between transactivating STAT1 and non-transactivating STAT6 for the N3 sites found in the promoters of sensitive genes (26). An analogous mechanism has been reported for inhibition of E-selectin gene transcription by IL-4, where STAT6 competes with NF-B for an overlapping binding site (37). A second hypothesis is that IL-4-activated STAT6 competes with STAT1 for limiting quantities of transcriptional coactivators such as the CREB-binding protein (CBP) (35). Previous studies have shown that repression of AP-1-dependent tr...

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Cytokines: Coordinators of Immune and Inflammatory Responses

Cited by 1,220 publications

References 0 publications

ETS1, NFκB and AP1 synergistically transactivate the human GM – CSF promoter

ETS1, NFκB and AP1 synergistically transactivate the human GM – CSF promoter

Raf/MAPK and rapamycin-sensitive pathways mediate the anti-apoptotic function of p21Ras in IL-3-dependent hematopoietic cells

Interleukin-4/STAT6 Represses STAT1 and NF-κB-dependent Transcription through Distinct Mechanisms

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