Divergent Effects of Interleukin-4 and Interferon-γ on Macrophage-Derived Chemokine Production: An Amplification Circuit of Polarized T Helper 2 Responses

Blood ◽  
1998 ◽  
Vol 92 (8) ◽  
pp. 2668-2671 ◽  
Author(s):  
Raffaella Bonecchi ◽  
Silvano Sozzani ◽  
Johnny T. Stine ◽  
Walter Luini ◽  
Giovanna D’Amico ◽  
...  
Keyword(s):  
Constitutive Expression ◽  
Interferon Γ ◽  
Interleukin 4 ◽  
Th2 Cells ◽  
Mrna Levels ◽  
T Helper ◽  
T Helper 1 ◽  
Chemokine Production ◽  
T Helper 2 ◽  
Ifn Γ

Macrophage-derived chemokine (MDC) is a CC chemokine that recognizes the CCR4 receptor and is selective for T helper 2 (Th2) versus T helper 1 (Th1) cells. The present study was designed to investigate the effect of the prototypic Th2/Th1 cytokines, interleukin-4 (IL-4) and interferon-γ (IFN-γ), on the production of MDC by human monocytes. IL-4 and IL-13 caused a time-dependent (plateau at 24 hours) and concentration-dependent (EC50 2 and 10 ng/mL, respectively) increase of MDC mRNA levels in monocytes. Increased expression of MDC mRNA was associated with protein release in the supernatant. MDC expression and production induced by IL-4 and IL-13 were inhibited by IFN-γ. IFN-γ also suppressed the constitutive expression of MDC in mature macrophages and dendritic cells. These results delineate an amplification loop of polarized Th2 responses based on differential regulation of MDC production by IL-4 and IL-13 versus IFN-γ and on the selectivity of this chemokine for polarized Th2 cells. © 1998 by The American Society of Hematology.

Divergent Effects of Interleukin-4 and Interferon-γ on Macrophage-Derived Chemokine Production: An Amplification Circuit of Polarized T Helper 2 Responses

Blood ◽  
1998 ◽  
Vol 92 (8) ◽  
pp. 2668-2671 ◽  
Author(s):  
Raffaella Bonecchi ◽  
Silvano Sozzani ◽  
Johnny T. Stine ◽  
Walter Luini ◽  
Giovanna D’Amico ◽  
...  
Keyword(s):  
Constitutive Expression ◽  
Interferon Γ ◽  
Interleukin 4 ◽  
Th2 Cells ◽  
Mrna Levels ◽  
T Helper ◽  
T Helper 1 ◽  
Chemokine Production ◽  
T Helper 2 ◽  
Ifn Γ

Abstract Macrophage-derived chemokine (MDC) is a CC chemokine that recognizes the CCR4 receptor and is selective for T helper 2 (Th2) versus T helper 1 (Th1) cells. The present study was designed to investigate the effect of the prototypic Th2/Th1 cytokines, interleukin-4 (IL-4) and interferon-γ (IFN-γ), on the production of MDC by human monocytes. IL-4 and IL-13 caused a time-dependent (plateau at 24 hours) and concentration-dependent (EC50 2 and 10 ng/mL, respectively) increase of MDC mRNA levels in monocytes. Increased expression of MDC mRNA was associated with protein release in the supernatant. MDC expression and production induced by IL-4 and IL-13 were inhibited by IFN-γ. IFN-γ also suppressed the constitutive expression of MDC in mature macrophages and dendritic cells. These results delineate an amplification loop of polarized Th2 responses based on differential regulation of MDC production by IL-4 and IL-13 versus IFN-γ and on the selectivity of this chemokine for polarized Th2 cells. © 1998 by The American Society of Hematology.

IL-4 synergistically enhances both IL-2– and IL-12–induced IFN-γ expression in murine NK cells

Blood ◽  
2003 ◽  
Vol 102 (1) ◽  
pp. 207-214 ◽  
Author(s):  
Jay H. Bream ◽  
Rafael E. Curiel ◽  
Cheng-Rong Yu ◽  
Charles E. Egwuagu ◽  
Michael J. Grusby ◽  
...  
Keyword(s):  
Nk Cells ◽  
Molecular Mechanisms ◽  
Synergistic Effects ◽  
Interferon Γ ◽  
Interleukin 4 ◽  
T Helper ◽  
T Helper 1 ◽  
Ifn Γ ◽  
Cytokine Stimulation ◽  
Positive Effect

Abstract Interleukin-4 (IL-4) is thought to influence T and natural killer (NK) cells by down-regulating T helper 1 (Th1)–type cytokines like interferon-γ (IFN-γ). While investigating IL-4 regulation of IFN-γ expression, we found that IL-4 synergized with IL-2 or IL-12 to enhance IFN-γ production and mRNA expression in spleen-derived, IL-2–cultured NK cells, as well as negatively sorted fresh DX5+/CD3- NK cells albeit at lower levels. The positive effect of IL-4 on IL-2–induced IFN-γ production was dependent upon signal transducer and activator of transcription 6 (Stat6) because this response was virtually abrogated in Stat6-/- mice. Notably, though, IL-12 plus IL-4 synergy on IFN-γ expression was intact in Stat6-/- mice. In exploring possible molecular mechanisms to account for the synergistic effects of IL-4 on murine NK cells, we found that IL-2 plus IL-4 stimulation resulted in a modest increase in tyrosine phosphorylation of Stat5, while IL-12 plus IL-4 treatment resulted in a more substantial increase in tyrosine-phosphorylated Stat4. Finally, to identify regions of the IFN-γ promoter that may be involved, NK cells from human IFN-γ promoter/luciferase transgenic mice were treated with cytokines. NK cells from proximal (-110 to +64) promoter region mice did not respond to cytokine stimulation; however, the intact -565 to +64 IFN-γ promoter responded synergistically to IL-2 plus IL-4 and to IL-12 plus IL-4 in NK cells. These data demonstrate a role for IL-4 in enhancing IFN-γ expression in murine NK cells that is partially dependent on Stat6 in IL-2 costimulation and completely independent of Stat6 in IL-12 costimulations. (Blood. 2003;102:207-214)

scholarly journals Regulation of the Interleukin (IL)-12R β2 Subunit Expression in Developing T Helper 1 (Th1) and Th2 Cells

1997 ◽  
Vol 185 (5) ◽  
pp. 817-824 ◽  
Author(s):  
Susanne J. Szabo ◽  
Anand S. Dighe ◽  
Ueli Gubler ◽  
Kenneth M. Murphy
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Th2 Cells ◽  
T Helper ◽  
T Helper 1 ◽  
Selective Loss ◽  
Th Cell ◽  
Subunit Expression ◽  
Ifn Γ

The developmental commitment to a T helper 1 (Th1)- or Th2-type response can significantly influence host immunity to pathogens. Extinction of the IL-12 signaling pathway during early Th2 development provides a mechanism that allows stable phenotype commitment. In this report we demonstrate that extinction of IL-12 signaling in early Th2 cells results from a selective loss of IL-12 receptor (IL-12R) β2 subunit expression. To determine the basis for this selective loss, we examined IL-12R β2 subunit expression during Th cell development in response to T cell treatment with different cytokines. IL-12R β2 is not expressed by naive resting CD4+ T cells, but is induced upon antigen activation through the T cell receptor. Importantly, IL-4 and IFN-γ were found to significantly modify IL-12 receptor β2 expression after T cell activation. IL-4 inhibited IL-12R β2 expression leading to the loss of IL-12 signaling, providing an important point of regulation to promote commitment to the Th2 pathway. IFN-γ treatment of early developing Th2 cells maintained IL-12R β2 expression and restored the ability of these cells to functionally respond to IL-12, but did not directly inhibit IL-4 or induce IFN-γ production. Thus, IFN-γ may prevent early Th cells from premature commitment to the Th2 pathway. Controlling the expression of the IL-12R β2 subunit could be an important therapeutic target for the redirection of ongoing Th cell responses.

Peripheral Blood T-Helper Cells and Eosinophil Populations in Patients with Atopic and Nonatopic Chronic Rhinosinusitis

2017 ◽  
Vol 31 (1) ◽  
pp. e8-e12 ◽  
Author(s):  
Zhenxiao Huang ◽  
Jayakar V. Nayak ◽  
Yan Sun ◽  
Qian Huang ◽  
Bing Zhou
Keyword(s):  
Chronic Rhinosinusitis ◽  
Peripheral Blood ◽  
T Helper Cells ◽  
Nasal Polyps ◽  
Interferon Γ ◽  
Interleukin 4 ◽  
Th2 Cells ◽  
T Helper ◽  
Helper Cells ◽  
Th1 And Th2

Background Analysis of recent research indicated that T-helper cells may play an important role in the pathogenesis of chronic rhinosinusitis (CRS) with nasal polyps (CRSwNP) and CRS without nasal polyps (CRSsNP). Objective The purpose of this study was to investigate the peripheral blood Th1 and Th2 cells and eosinophil population in patients with CRS. Methods Peripheral blood samples were obtained from nine nonatopic controls, 37 patients with CRSsNP, and 66 patients with CRSwNP. The samples were then analyzed by flow cytometry analysis (Th1 cell [CD4+, interleukin 4−, interferon γ+]; and Th2 cell [CD4+, interleukin 4+, interferon γ−]). The patients were stratified into four groups based on their allergic status by using skin-prick test results and immunoglobulin E level measurements as the following: (1) nonatopic CRSsNP, (2) nonatopic CRSwNP, (3) atopic CRSsNP, and (4) atopic CRSwNP. Eosinophil counts were also compared. The severity of nasal diseases in these patients was assessed via the Lund-Mackay score. Results No significant differences in peripheral blood Th1 and Th2 cells were found among all the atopic, nonatopic CRS groups, and the nonatopic control groups. Peripheral blood eosinophil levels in atopic CRSwNP were significantly elevated compared with the nonatopic controls (p < 0.05), but no significant difference was found among all atopic and nonatopic CRS groups. Conclusion Analysis of our data demonstrated that a proportion of systemic Th1- and Th2-skewed lymphocytes in all CRS groups were similar to that in healthy subjects, irrespective of atopic status. The patients with CRSwNP and with atopy but not the patients with CRSsNP and with atopy demonstrated systemic eosinophilic inflammation. Further studies are needed to investigate underlying pathophysiologic mechanism or endotypes.

scholarly journals Modulation of T helper 1 and T helper 2 immune balance in a stress mouse model during Chlamydia muridarum genital infection

2019 ◽  
Author(s):  
Tesfaye Belay ◽  
Elisha Martin ◽  
Gezelle Brown ◽  
Raenel Crenshaw ◽  
Julia Street ◽  
...  
Keyword(s):  
Mouse Model ◽  
Genital Infection ◽  
Th2 Cytokines ◽  
T Helper ◽  
T Helper 1 ◽  
Chlamydia Muridarum ◽  
T Helper 2 ◽  
Induced Stress ◽  
Ifn Γ ◽  
Th1 And Th2

ABSTRACTA mouse model to study the effect of cold-induced stress on Chlamydia muridarum genital infection and immune response has been developed in our laboratory. Our previous results show that cold-induced stress increases the intensity of chlamydia genital infection, but little is known about the effect of cold-induced stress on differentiations and activities of T cell subpopulations and bone marrow derived dendritic cells (BMDCs). The factors that regulate the production of T helper 1 (Th1) or T helper 2 (Th2) cytokines is not clear. The objective of this study was to examine whether cold-induced stress modulates the expression of transcription factors and hallmark cytokines of Th1 and Th2 or differentiation of BMDCs during C. muridarum genital infection in mice. Our results show that mRNA level of beta2-adrenergic receptor (β2-AR) compared to β1-AR and β3-AR was high in mixed population of CD4+ T cells and BMDCs. Further, decreased expression of T-bet and low level of interferon-gamma (IFN-γ) production and increased expression of GATA-3 and interleukin-4 (IL-4) production in CD4+ T of stressed mice was observed. Exposure of BMDCs to feroterol (β2-AR agonist) or ICI,118551 (β2-AR antagonist), respectively, revealed significant stimulation or inhibition of β2-AR in stressed mice. Moreover, co-culturing of mature BMDC and naïve CD4+ T cells resulted in increased production of IL-4, IL-10, and IL-17 in culture supernatants, suggesting that stimulation of β2-AR leads to the increased production of Th2 cytokines. Overall, our results show for the first time that cold-induced stress is able to modulate the pattern of Th1 and Th2 cytokine environment, suggesting that it promotes the differentiation to Th2 rather than Th1 by the overexpression of GATA-3 correlated with elevated production of IL-4, IL-10, IL-23, and IL-17 in contrast to a low expression of T-bet correlated with less IFN-γ secretion in the mouse model.

Selective disruption of interleukin 4 autocrine-regulated loop by a tyrosine kinase inhibitor restricts activity of T-helper 2 cells

Blood ◽  
2000 ◽  
Vol 95 (12) ◽  
pp. 3816-3822 ◽  
Author(s):  
Li Hua Wang ◽  
Robert A. Kirken ◽  
Xiao Yi Yang ◽  
Rebecca A. Erwin ◽  
Luis DaSilva ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Cell Line ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Inhibitory Effect ◽  
Interleukin 4 ◽  
Th2 Cells ◽  
T Helper ◽  
Th1 Cell ◽  
T Helper 2

Interleukin (IL) 4 is a potent immunomodulatory cytokine secreted by T-helper 2 (Th2) cells and Th2 mast cells that promotes the commitment of cells. However, unregulated production and release of IL-4 can exacerbate allergic reactions and increase susceptibility to infectious organisms and viruses. Here, we present evidence that AG-490, a Janus tyrosine kinase (JAK) 2-JAK3 inhibitor, effectively blocked IL-4 gene expression and secretion in the Th2 cell line D10 that was not occurring after anti-CD3 antibody stimulation, whereas AG-490 had no inhibitory effect on production of other Th2 cytokines or cytokines synthesized by the corresponding Th1 cell line clone 29. AG-490 potently inhibited IL-4–mediated proliferation of both D10 and the IL-4–dependent cell line CT.4S. Moreover, AG-490 markedly inhibited IL-4 activation of JAK3 and blocked the downstream activation of signal transducer and activator of transcription 6, as judged by tyrosine phosphorylation, DNA binding, and transcription assays. In contrast, AG-490 did not affect tumor necrosis factor  activation of NF-κB at similar concentrations of drug. These data suggest that tyrosine kinase inhibitors that inhibit JAK3 may have previously unrecognized and selective clinical potential as immunotherapeutic drugs to treat Th2-mediated diseases driven by IL-4.

scholarly journals Lymphokine-mediated regulation of the proliferative response of clones of T helper 1 and T helper 2 cells.

1988 ◽  
Vol 168 (2) ◽  
pp. 543-558 ◽  
Author(s):  
R Fernandez-Botran ◽  
V M Sanders ◽  
T R Mosmann ◽  
E S Vitetta
Keyword(s):  
Proliferative Response ◽  
Th2 Cells ◽  
Th1 Cells ◽  
T Helper ◽  
T Helper 1 ◽  
Ifn Gamma ◽  
T Helper 2 ◽  
Regulatory Interactions ◽  
Th Cell ◽  
Th1 And Th2

Murine Th1 and Th2 subsets differ not only in the lymphokines they produce, but also functionally. It is not clear what factors influence the preferential activation of one subset versus the other and what regulatory interactions exist between them. The purpose of this study was to examine the effect of lymphokines produced by clones of Th1 cells (IL-2 and IFN-gamma), Th2 cells (IL-4), and APC (IL-1) on the proliferative response of Th1 and Th2 cells after antigenic stimulation. Activation of both types of clones in the presence of antigen and APC resulted in the acquisition of responsiveness to the proliferative effects of both IL-2 and IL-4, although Th2 cells were more responsive to IL-4 than Th1 cells. Responsiveness of Th1 and Th2 cells to both lymphokines decreased with time after initial antigenic activation; Th1 cells lost their responsiveness to IL-4 more rapidly and to IL-2 more slowly than Th2 cells. IFN-gamma partially inhibited the IL-2 and IL-4-mediated proliferation of Th2, but not Th1 cells. Although the presence of IL-1 was not required for the response of Th1 or Th2 cells to IL-4, its presence resulted in a synergistic effect with IL-2 or IL-4 in Th2 but not in Th1 cells. Both subsets responded to a mixture of IL-2 and IL-4 in synergistic fashion. Delayed addition and wash-out experiments indicated that both IL-2 and IL-4 had to be present simultaneously in order for synergy to occur. These results suggest that Th cell subsets might regulate each other via the lymphokines that they secrete and that the pathways of IL-2 and IL-4 mediated proliferation are interrelated.

scholarly journals A role for CCR4 in development of mature circulating cutaneous T helper memory cell populations

2005 ◽  
Vol 201 (7) ◽  
pp. 1045-1051 ◽  
Author(s):  
Espen S. Baekkevold ◽  
Marc-André Wurbel ◽  
Pia Kivisäkk ◽  
Clare M. Wain ◽  
Christine A. Power ◽  
...  
Keyword(s):  
T Cells ◽  
Memory Cell ◽  
Interferon Γ ◽  
Interleukin 4 ◽  
Th2 Cells ◽  
T Helper ◽  
Th Cells ◽  
Selectin Ligand ◽  
Rag 1 ◽  
Chemokine Receptor Ccr4

Expression of the chemokine receptor CCR4 is strongly associated with trafficking of specialized cutaneous memory T helper (Th) lymphocytes to the skin. However, it is unknown whether CCR4 itself participates in the development of cutaneous Th populations. We have addressed this issue via competitive bone marrow (BM) reconstitution assays; equal numbers of BM cells from CCR4+/+ and CCR4−/− donors were allowed to develop side-by-side within RAG-1−/− hosts. Cells from both donor types developed equally well into B cells, naive CD8 T cells, naive CD4 T cells, interferon-γ+ Th1 cells, and interleukin-4+ Th2 cells. In marked contrast, circulating cutaneous memory Th cells (i.e., E-selectin ligand+ [E-lig+]) were more than fourfold more likely to be derived from CCR4+/+ donors than from CCR4−/− donors. Most of this effect resides within the CD103+ subset of the E-lig+ Th population, in which donor CCR4+/+ cells can outnumber CCR4−/− cells by &gt;12-fold. No similar effect was observed for α4β7+ intestinal memory Th cells or CD103+/E-lig− Th cells. We conclude that CCR4 expression provides a competitive advantage to cutaneous Th cells, either by participating in their development from naive Th cells, or by preferentially maintaining them within the memory population over time.

Constitutive expression of interleukin 4 in vivo does not lead to the development of T helper 2 type CD8+ T cells secreting interleukin 4 or interleukin 5

1999 ◽  
Vol 68 (2-3) ◽  
pp. 383-390 ◽  
Author(s):  
Klaus Josef Erb ◽  
Sam Hou ◽  
Lisa Hyland ◽  
Joanna Kirman ◽  
Heidrun Moll ◽  
...  
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Constitutive Expression ◽  
Interleukin 4 ◽  
T Helper ◽  
Interleukin 5 ◽  
T Helper 2
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