Delicate balance of Th1 vs TH2 is regualted by their respective cytokines as opposed to cell to cell interaction

J Immunol. 1998 Jun 1;160(11):5347-54.

Alternative metabolic states in murine macrophages reflected by the nitric oxide synthase/arginase balance: competitive regulation by CD4+ T cells correlates with Th1/Th2 phenotype.

Munder M¹, Eichmann K, Modolell M.

 

 

Abstract

Activated murine macrophages metabolize L-arginine via two main pathways that are catalyzed by the inducible enzymes nitric oxide synthase (iNOS) and arginase. We have previously shown that CD4+ T cell-derived cytokines regulate a competitive balance in the expression of both enzymes in macrophages; Thl-type cytokines induce iNOS while they inhibit arginase, whereas the reverse is the case for Th2-type cytokines. Here we addressed the regulation of both metabolic pathways by CD4+ T cells directly. Macrophages were used as APCs for established Th1 and Th2 T cell clones as well as for in vitro polarized Th1 or Th2 T cells of transgenic mice bearing an MHC class II-restricted TCR. Both systems revealed a similar dichotomy in the macrophages; Th1 T cells led to an exclusive induction of iNOS, whereas Th2 T cells up-regulated arginase without inducing iNOS. Arginase levels induced by Th2 T cells far exceeded those inducible by individual Th2 cytokines. Similarly, high arginase levels could be induced by supernatants of Th2 cells stimulated in various ways. Ab blocking experiments revealed the critical importance of IL-4 and IL-10 for arginase up-regulation. Finally, strong synergistic effects between IL-4/IL-13 and IL-10 were observed, sufficient to account for the extraordinarily high arginase activity induced by Th2 cells. Our results suggest that the iNOS/arginase balance in macrophages is competitively regulated in the context of Th1- vs Th2-driven immune reactions, most likely by cytokines without the requirement for direct cell interaction.

Intact Urea Cycle in face of Arginine is required for antiinflammatory balance in TH2 expression. Antiflammatory index could be Th1/Th2 ratio .

This dichotomy also characterizes two alternative states that are often correlated with the course of a disease. The Th1 cytokines are considered proinflammatory cytokines, and they are often correlated with a gaseous messenger known to modulate specific functions of cell populations involved in the immune response. This messenger is nitric oxide (NO), a gaseous metabolite produced by the degradation of amino acid l-arginine by nitric oxide synthase (NOS). NO has been shown to be a crucial host-protective and antimicrobial effector molecule as well as a potential host-destructive mediator in diverse scenarios of immunopathology. Nevertheless, l-arginine may be metabolized by an alternative metabolic pathway. It can also be catalyzed by arginase, which converts l-arginine to l-ornithine and urea. Th2, in contrast to Th1 cytokines, often exhibits anti-inflammatory properties, and their expression has been related to the induction of arginase.

Note that as  arginase is stimulated which promotes Th2, anti-inflammatory activity, ornithine is produced, which of course can be eliminated by the Urea Cycle. If Urea cycle is dysfunctional ornithine backs up and obviously pushes back on arginase performance. This pushes arginine toward inflammatory lines with inducible nitric Acid synthase. This of course could be the explanation of the pathology in the Hepato-renal syndrome

AMIE implementation report: Breast Cancer : In survival analysis, absolute numbers of TILs do not represent major prognostic indicators a ratio > 1 of total FOXP3+/CD4+ TILs

subject: Ductal and lobular breast cancers appear to be infiltrated by different lymphocyte subpopulations. In ductal cancers increased CD4+ and FOXP3+ TIL numbers are associated with more aggressive tumor features. In survival analysis, absolute numbers of TILs do not represent major prognostic indicators in ductal and lobular breast cancer. Remarkably however, a ratio > 1 of total FOXP3+/CD4+ TILs in ductal carcinoma appears to represent an independent favorable prognostic factor.
object_opposite: Ratio < 1 of total FOXP3+/CD4+ TILs in ductal carcinoma appears to represent an independent unfavorable prognostic factor.
misc: Tumor-infiltrating lymphocytes (TILs) are frequently considered to reflect host immune response against malignant tumors [1]. TILs have been shown to infiltrate a variety of tumors of diverse histological origin [2,3]. Their exquisite tumor specificity has been demonstrated in a number of cases and it has led to the characterization of tumor associated antigens. Although resident TILs have frequently been reported to be in a functionally "anergic" state [4,5], importantly, following "ex vivo" culture, TILs have been used to treat different types of cancers [6]. In line with these data, tumor infiltration by T lymphocytes has been shown to be associated with favorable prognosis, particularly in melanoma and colorectal cancers [2,7]. On the other hand, tumor infiltration by T-lymphocytes subsets endowed with immuno-regulatory or suppressive potential, e.g. CD4+ T-cells expressing FOXP3 transcription factor, has been suggested to be associated with tumor progression and unfavorable prognosis [8]. More recently, a CD4+ T-cell subset producing IL-17 has been implicated in the pathogenesis of several autoimmune diseases [9]. However, the role of the so-called Th17 in antitumor immunity is still debated [10-13]
author_year: Raoul Droeser/Inti Zlobec/ Ergin Kilic / Uwe Güth/ Michael Heberer/, Giulio Spagnoli/ Daniel Oertli1 / Coya Tapia/2012
journal_volume_page: http://1.usa.gov/1DWHklJ BMC Cancer / 12/134

AMIE /TH17 /regulatory examples

subject: chagas + extent of myocardiopathy Deficient regulatory T cell activity and low frequency of IL-17-producing T cells
object_opposite: 1L17/Deficient regulatory T cell activity and low frequency of IL-17-producing T cells
misc: Deficient regulatory T cell activity and low frequency of IL-17-producing T cells correlate with the extent of cardiomyopathy in human Chagas' disease/Myocardium damage during Chagas' disease results from the immunological imbalance between pro- and production of anti-inflammatory cytokines and has been explained based on the Th1-Th2 dichotomy and regulatory T cell activity. Recently, we demonstrated that IL-17 produced during experimental T. cruzi infection regulates Th1 cells differentiation and parasite induced myocarditis. Here, we investigated the role of IL-17 and regulatory T cell during human Chagas' disease.
author_year: Authors: Guedes PM, /Gutierrez FR, /Silva GK, Dellalibera-Joviliano R, /Rodrigues GJ,/ Bendhack LM, Rassi A,/ Rassi A, /Schmidt A, /Maciel BC, /Marin Neto JA/
journal_volume_page: pubmed 6(4): e1630

AMIE implementation

subject: We show that Teff and Treg require distinct metabolic programs to support these functions. Th1, Th2, and Th17 cells expressed high surface levels of the glucose transporter Glut1 and were highly glycolytic
object_opposite: Treg, in contrast, expressed low levels of Glut1 and had high lipid oxidation rates. Consistent with glycolysis and lipid oxidation promoting Teff and Treg, respectively, Teff were selectively increased in Glut1 transgenic mice and reliant on glucose metabolism, whereas Treg had activated AMP-activated protein kinase and were dependent on lipid oxidation. Importantly, AMP-activated protein kinase stimulation was sufficient to decrease Glut1 and increase Treg generation in an asthma model
misc: Cutting Edge: Distinct Glycolytic and Lipid Oxidative Metabolic Programs Are Essential for Effector and Regulatory CD4+ T Cell Subsets
author_year: Ryan D. Michalek/ Valerie A. Gerriets/ Sarah R. Jacobs/ Andrew N. Macintyre/ Nancie J. MacIver/ Emily F. Mason/ Sarah A. Sullivan/ Amanda G. Nichols/ Jeffrey C. Rathmell/2011
journal_volume_page: Journal of Immunology/10/4049