1: J Immunol. 2005 Jul 1;175(1):566-74. 

5-aminoimidazole-4-carboxamide ribonucleoside: a novel immunomodulator with
therapeutic efficacy in experimental autoimmune encephalomyelitis.

Nath N, Giri S, Prasad R, Salem ML, Singh AK, Singh I.

Department of Pediatrics, Medical University of South Carolina, Charleston, SC
29425, USA.

Experimental autoimmune encephalomyelitis (EAE), an animal model of multiple
sclerosis, is a Th1-mediated inflammatory demyelinating disease of the CNS.
AMP-activated protein kinase was reported recently to have anti-inflammatory
activities by negatively regulating NF-kappaB signaling. In this study, we
investigated the prophylactic and therapeutic efficacy of an AMP-activated
protein kinase activator, 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR),
in active and passive EAE induced by active immunization with PLP(139-151) or
MOG(35-55) and in adoptive transfer of PLP(139-151)-sensitized T cells,
respectively. In vivo treatment with AICAR exerted both prophylactic and
therapeutic effects on EAE, attenuating the severity of clinical disease. The
anti-inflammatory effects of AICAR were associated with the inhibition of the
Ag-specific recall responses and inhibition of the Th1-type cytokines IFN-gamma
and TNF-alpha, whereas it induced the production of Th2 cytokines IL-4 and
IL-10. Treatment of PLP(139-151)-specific T cells in vitro with AICAR decreased
their expression of T-bet in response to IL-12, a Th1 transcription factor,
whereas in response to IL-4, it induced the expression and phosphorylation of
Th2 transcription factors GATA3 and STAT6, respectively. Moreover, treatment of
APCs in vitro with AICAR inhibited their capability to present the proteolipid
protein peptide to PLP(139-151)-specific T cells. In an irrelevant Th1-mediated,
OT-2 TCR transgenic mouse model, AICAR impaired in vivo Ag-specific expansion of
CD4(+) T cells. Together, these findings show for the first time that AICAR is a
novel immunomodulator with promising beneficial effects for the treatment of
multiple sclerosis and other Th1-mediated inflammatory diseases.

PMID: 15972693 [PubMed - indexed for MEDLINE]


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2: Infect Immun. 2005 Jun;73(6):3394-401. 

Transcriptional control of impaired Th1 responses in patent lymphatic filariasis
by T-box expressed in T cells and suppressor of cytokine signaling genes.

Babu S, Kumaraswami V, Nutman TB.

Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious
Diseases/NIH, 4 Center Drive, Room 4/B1-05, Bethesda, MD 20892-0425, USA.
sbabu@niaid.nih.gov

T-bet (T-box expressed in T cells) and GATA-3 are transcription factors that
play a critical role in the development of Th1 and Th2 cells, as do genes of the
SOCS (suppressor of cytokine signaling) family, albeit indirectly. Another
transcription factor, Foxp3, is a master regulator of natural regulatory T cells
(Tregs). To identify the role of these factors in impaired Th1 responses of
patent filarial infection, analysis of cytokine, SOCS, and transcription factor
mRNA expression was performed on purified T cells of filaria-infected
individuals (n = 6) and uninfected controls (n = 6). As expected (and in
contrast to cells of uninfected individuals), there was a significant depression
of gamma interferon (IFN-gamma) and a concomitant increase in interleukin-4
(IL-4), IL-5, and IL-10 mRNA expression following stimulation with parasite
antigen (BmA) but not with a polyclonal T-cell (anti-CD3) stimulus. T-bet (but
not GATA-3) was expressed at significantly lower levels in cells of
filaria-infected individuals in response to BmA compared with those from the
uninfected group, accounting, at least partially, for the diminished IFN-gamma
expression. Second, we found no significant differences in expression of Foxp3
between the two groups, although induction of Foxp3 expression correlated with
induced expression levels of IL-10, implicating Tregs in the IL-10 expression
seen. Finally, parasite-specific T-cell expression of SOCS-1, SOCS-5, and SOCS-7
was significantly diminished among infected patients; in contrast, expression of
SOCS-3 increased. Our data therefore indicate that the impaired Th1 responses
observed in patent lymphatic filariasis are associated with decreased expression
of T-bet, SOCS-1, SOCS-5, and SOCS-7 and increased expression of SOCS-3 in T
cells.

PMID: 15908366 [PubMed - indexed for MEDLINE]


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3: FEMS Immunol Med Microbiol. 2005 Apr 1;44(1):43-50. 

Altered T helper 1 reaction but not increase of virus load in patients with
dengue hemorrhagic fever.

Chen RF, Liu JW, Yeh WT, Wang L, Chang JC, Yu HR, Cheng JT, Yang KD.

Department of Biological Sciences, National Sun Yat-sen University, Kaohsiung,
Taiwan.

To investigate whether dengue-2 patients with and without dengue hemorrhagic
fever had different virus load, immune mediators, or T helper (Th) reaction, we
simultaneously measured virus load, immune mediators and the Th1/Th2
transcription factors T-bet/GATA-3 mRNA expression in a large outbreak of
dengue-2 infections in Southern Taiwan. Results showed that virus load was not
significantly different between patients with and without dengue hemorrhagic
fever. Patients with dengue fever had higher IFN-gamma levels, but patients with
dengue hemorrhagic fever had significantly higher IL-10 levels. Further studies
showed that patients with dengue hemorrhagic fever had a significantly lower
T-bet than those with dengue fever, but GATA-3 mRNA expression in peripheral
blood leukocytes was not significant difference between both groups. In
conclusion, altered Th1 reaction as reflected by lower T-bet mRNA expression
associated with higher IL-10 levels might be involved in the pathogenesis of
dengue hemorrhagic fever.

PMID: 15780577 [PubMed - indexed for MEDLINE]


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4: J Immunol. 2005 Mar 15;174(6):3227-36. 

Heat shock protein 60 inhibits Th1-mediated hepatitis model via innate
regulation of Th1/Th2 transcription factors and cytokines.

Zanin-Zhorov A, Bruck R, Tal G, Oren S, Aeed H, Hershkoviz R, Cohen IR, Lider O.

Department of Immunology, Weizmann Institute of Science, Rehovot, Israel.

Extracellular heat shock protein 60 (HSP60) has been considered a
proinflammatory danger signal. Yet, HSP60 can also down-regulate experimental
immune arthritis and diabetes models by specific inhibition of Th1-like
responses. We now report that HSP60 in vitro differentially modulates the
expression of Th1/Th2 transcription factors in human T cells: HSP60
down-regulates T-bet, NF-kappaB, and NFATp and up-regulates GATA-3, leading to
decreased secretion of TNF-alpha and IFN-gamma and enhanced secretion of IL-10.
These effects depended on TLR2 signaling and could not be attributed to LPS or
to other contaminants. In BALB/c mice, HSP60 in vivo inhibited the clinical,
histological, and serological manifestations of Con A-induced hepatitis
associated with up-regulated T cell expression of suppressor of cytokine
signaling 3 and GATA-3 and down-regulated T-bet expression. These results
provide a molecular explanation for the effects of HSP60 treatment on T cell
inflammation via innate regulation of the inflammatory response.

PMID: 15749853 [PubMed - indexed for MEDLINE]


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5: Zhonghua Yi Xue Za Zhi. 2004 Sep 17;84(18):1562-6. 

[Preventive effect of anterior chamber associated immune deviation on
endotoxin-induced uveitis]

[Article in Chinese]

Fu T, Yang PZ, Huang XK, Zhou HY, Li FF, Huang Q.

Beijing Tongren Eye Center, Tongren Hospital, Capital University of Medical
Science, Beijing 100730, China.

OBJECTIVE: To determine the effect of anterior chamber associated immune
deviation (ACAID) on endotoxin-induced uveitis (EIU) and the possible mechanism.
METHODS: ACAID animal model was induced by injection of 5 microl IRBP (10
microg/microl) into the anterior chamber (AC) of Spar-Dawley (SD) rats. Then 200
microg LPS was injected into hind footpads at different time points after AC
inoculation. The animals were randomly divided into 3 groups: positive control
(LPS injection only), 3 d group (LPS injection 3 days after IRBP inoculation), 7
d group (LPS injection 7 days after IRBP inoculation). Delayed type
hypersensitivity (DTH) was examined to determine the development of ACAID. Then
the serum level of IL-10 was evaluated by ELISA, and GATA-3 expression at the
different time points after IRBP injection was assayed by reverse transcription
polymerase chain reaction (RT-PCR) and Western blot on mRNA and protein level
respectively. The ocular inflammation was observed clinically; at the same time,
the eye was extirpated and histological examination was performed. RESULTS: In
control and 3 d groups, significant DTH reaction was induced, but the serum
level of IL-10 could not be detected and GATA-3 expression was not increased.
While in 7 d group, the DTH reaction could not be induced, and IL-10 and GATA-3
expression increased significantly at both the mRNA and protein levels. The
clinical manifestation was significantly alleviated in the 7 d group;
Histological examination displayed that the inflammatory cells were
significantly reduced in iris/ciliary body, anterior and posterior chambers,
vitreous body and retina of the rats in 7 d group. CONCLUSION: The development
of ACAID can reduce the ocular inflammation induced by LPS, that is related to
the increase of GATA-3 and IL-10 expression.

PMID: 15500722 [PubMed - indexed for MEDLINE]


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6: Oncol Rep. 2003 Sep-Oct;10(5):1507-12. 

Traditional Chinese medicine Astragalus reverses predominance of Th2 cytokines
and their up-stream transcript factors in lung cancer patients.

Wei H, Sun R, Xiao W, Feng J, Zhen C, Xu X, Tian Z.

School of Life Sciences, University of Science and Technology of China, Hefei
City, Anhui 230027, P.R. China.

Th2 cytokine is predominant in tumor patients and was found to be associated
with tumor progression. Reversing of Th2 dominant status is thought to be a
promising strategy. In the present study, peripheral blood mononuclear cells
(PBMNC) of 37 lung cancer patients and 19 healthy subjects were prepared and
used for examination of cytokine secretion and gene expression. The positive
percentage of mRNA transcripts of Th1 cytokines (8.1% for IFNgamma and 13.5% for
IL-2) in patients' PBMNC were lower than those of Th2 cytokines (70.3% for IL-4,
64.9% for IL-6 and 83.8% for IL-10). The gene expression capacity (measured as
relative intensity to ratio of beta-actin) of patients for Th1 cytokines was
low, but constitutively relatively high for Th2 cytokines. Both positive
percentage and relative intensity were lower in transcript factor for Th1
cytokine, T-bet (40.5% and 0.139, respectively) than those for Th2 cytokine,
GATA3 (89.2% and 0.364, respectively). Traditional Chinese medicine, Astragalus
(AG) was observed to reverse Th2 status of lung cancer. AG enhanced culture
supernatant and gene expression levels of Th1 cytokine (IFNgamma and IL-2) and
its transcript factor (T-bet), and reduced those of Th2 cytokines in cultured
PBMNC of lung cancer patients. These results demonstrated that traditional
Chinese medicine AG might reverse the Th2 predominant status in lung cancer
patients, which is a probable alternative therapeutic regime in future.

PMID: 12883732 [PubMed - indexed for MEDLINE]


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7: Int Immunol. 2003 Aug;15(8):1017-25. 

Retinoic acids exert direct effects on T cells to suppress Th1 development and
enhance Th2 development via retinoic acid receptors.

Iwata M, Eshima Y, Kagechika H.

Mitsubishi Kagaku Institute of Life Sciences, 11 Minamiooya, Machida-shi, Tokyo
194-8511, Japan. iwata@libra.Is.m-kagaku.co.jp

The vitamin A metabolite, retinoic acid (RA), affects Th1 and Th2 development.
The effect is partly exerted through the modulation of antigen-presenting cell
functions, but it remains unclear whether RA directly exerts its effect on T
cells to influence Th1/Th2 development. To clarify this problem, we used two
experimental systems with isolated T cells in vitro. In one system, isolated
CD4+CD8+ thymocytes differentiated into Th1 and Th2 by two transient
stimulations with defined combinations of ionomycin and phorbol myristate
acetate followed by treatment with IL-2 and IL-4 and/or IL-12. In the second
system, functional differentiation was induced in purified naive CD4 T cells
from DO-11.10 TCR-transgenic and RAG-2-deficient mice with cytokines and
antibodies to CD3 and CD28. In both systems, all-trans-RA at > or = 1 nM
concentrations suppressed Th1 development, but enhanced Th2 development.
9-cis-RA elicited similar effects. The optimal enhancement of Th2 development in
the second system, however, was achieved with a delayed addition of RA. The
presence of RA during the initial stimulation period often suppressed Th2
development. The RA receptor (RAR) antagonists, LE540 and LE135, but not the
retinoic X receptor (RXR) antagonist, PA452, inhibited the effect of RA on
Th1/Th2 development. Accordingly, the RAR agonists, Am80 and Tp80, but not the
RXR agonists, HX600 and TZ335, mimicked the effect of RA. The RXR agonists
enhanced the effect of the RAR agonists only slightly, if at all. These results
indicate that, via RAR, RA directly suppresses Th1 development and directly
enhances Th2 development with its timely addition.

PMID: 12882839 [PubMed - indexed for MEDLINE]


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8: Nat Rev Immunol. 2002 Dec;2(12):933-44. 

The lineage decisions of helper T cells.

Murphy KM, Reiner SL.

Howard Hughes Medical Institute and Department of Pathology and Immunology,
Washington University School of Medicine, St Louis, Missouri 63110, USA.
murphy@pathbox.wustl.edu

After encountering antigen, helper T (T(H)) cells undergo differentiation to
effector cells, which can secrete high levels of interferon-gamma, interleukin-4
(IL-4), IL-10 and other immunomodulators. How T(H) cells acquire, and remember,
new patterns of gene expression is an area of intensive investigation. The
process is remarkably plastic, with cytokines being key regulators. Extrinsic
signals seem to be integrated into cell-intrinsic programming, in what is
becoming an intriguing story of regulated development. We summarize the latest
insights into mechanisms that govern the lineage choices that are made during
T(H)-cell responses to foreign pathogens.

Publication Types:
    Review
    Review, Tutorial

PMID: 12461566 [PubMed - indexed for MEDLINE]


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9: J Immunol. 2002 Sep 1;169(5):2498-506. 

Cytokine coexpression during human Th1/Th2 cell differentiation: direct evidence
for coordinated expression of Th2 cytokines.

Cousins DJ, Lee TH, Staynov DZ.

Department of Respiratory Medicine and Allergy, GKT School of Medicine, King's
College, London, United Kingdom. david.cousins@kcl.ac.uk

We have developed an in vitro differentiation assay in which human naive CD4(+)
cells are driven toward either the Th1 or Th2 phenotype. We have examined the
interrelationships among the expression of IL-2, IL-4, IL-5, IL-10, IL-13,
GM-CSF, and IFN-gamma in individual cells using intracellular cytokine staining
at various times during the differentiation process. We provide direct evidence
that the Th2 cytokines IL-4, IL-5, and IL-13, unlike the other cytokines, are
regulated by a coordinated mechanism. We also show that IL-10 is expressed by a
different subset of cells that is prevalent at early stages of Th2
differentiation, but then diminishes. Additionally we demonstrate that while
naive cells can express IL-2 upon activation, they cannot express GM-CSF.
Commitment to GM-CSF expression occurs during differentiation in a Th1/Th2
subset-independent manner. Furthermore, we have examined the levels of GATA3,
c-Maf, T-bet, and Ets-related molecule during human Th1/Th2 differentiation and
suggest that differences in the levels of these critical transcription factors
are responsible for commitment toward the Th1 or Th2 lineage.

PMID: 12193719 [PubMed - indexed for MEDLINE]


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10: Curr Biol. 2002 Jan 8;12(1):35-45. 

Physical and functional interaction between GATA-3 and Smad3 allows TGF-beta
regulation of GATA target genes.

Blokzijl A, ten Dijke P, Ibanez CF.

Division of Molecular Neurobiology, Department of Neuroscience, Karolinska
Institute, 171 77, Stockholm, Sweden.

BACKGROUND: Members of the GATA family of zinc finger transcription factors are
genetically controlled "master" regulators of development in the hematopoietic
and nervous systems. Whether GATA factors also serve to integrate epigenetic
signals on target promoters is, however, unknown. The transforming growth
factor-beta (TGF-beta) superfamily is a large group of phylogenetically
conserved secreted factors controlling cell proliferation, differentiation,
migration, and survival in multiple tissues. RESULTS: GATA-3, a key regulator of
T helper cell development, was found to directly interact with Smad3, an
intracellular signal transducer of TGF-beta. Complex formation required a
central region in GATA-3 and the N-terminal domain of Smad3. GATA-3 mediated
recruitment of Smad3 to GATA binding sites independently of Smad3 binding to
DNA, and the two factors cooperated synergistically to regulate transcription
from the IL-5 promoter in a TGF-beta-dependent manner. Treatment of T helper
cells with TGF-beta promoted the formation of an endogenous Smad3/GATA-3 nuclear
complex and stimulated production of the Th2 cytokine IL-10 in a Smad3- and
GATA-3-dependent manner. CONCLUSIONS: Although Smad proteins are known to
interact with a number of general transcription factors, these are insufficient
to explain the tissue-specific biology of TGF-beta proteins. Through its
interaction with Smad3, GATA-3 is able to integrate a genetic program of cell
differentiation with an extracellular signal, providing a molecular framework
for the effects of TGF-beta on the development and function of specific subsets
of immune cells and possibly other cell types.

PMID: 11790301 [PubMed - indexed for MEDLINE]


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11: Brain Res. 2000 Jul 7;870(1-2):27-35. 

Developmentally regulated gene expression of Th2 cytokines in the brain.

Lovett-Racke AE, Smith ME, Arredondo LR, Bittner PS, Ratts RB, Shive CL,
Forsthuber TG, Racke MK.

Department of Neurology, Washington University School of Medicine, St. Louis,
MO, USA. alovet@mednet.swmed.edu

Given the critical role of cytokines in the regulation of an inflammatory
response, we investigated whether certain cytokines are expressed in the brains
of normal mice during maturation that could contribute to the immune-privileged
nature of the CNS or potentially influence an immune-mediated illness such as
experimental allergic encephalomyelitis. The gene expression of IFN gamma (Th1
cytokine) and IL-4 (Th2 cytokine) was analyzed in the brain of several strains
of mice. IFN gamma was not detectable. However, IL-4 was present in the brains
of neonatal mice, but not adult mice. Resident CNS cells are believed to be the
source of the IL-4, because mice deficient in T cells (SCID and RAG2-/-)
expressed the IL-4 gene in the CNS. Further analysis indicated that the gene
expression of the Th2 cytokine transcription factor, GATA-3, correlated with
IL-4 and IL-10 expression in the brain. Since GATA-3-deficient mice have an
abnormal CNS, brain-derived Th2 cytokines may play an important role in CNS
development, as well as potentially contribute to the immune-privileged nature
of the brain.

PMID: 10869498 [PubMed - indexed for MEDLINE]


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