Th1, Th2, and Th3 cytokine alterations in major depression

BACKGROUND: Many studies have shown that the balance between Th1 cytokines and Th2 cytokines plays a role in modulation of cellular responses in the brain during psychological stress and psychiatric disorders. The Th3 cytokine, transforming growth factor beta-1 (TGF-beta1), has been shown to regulate the balance between Th-1 and Th-2 cytokines. However, the role of TGF-beta1 in the psychoimmunology of depression has never been explored. METHODS: A total of 40 depressed patients and 80 normal controls were recruited. The plasma levels of IFN-gamma, IL-4, and TGF-beta1 were studied at the time of admission and 8 weeks after antidepressant treatment. RESULTS: The proportion of patients who showed immunoreactivity to IFN-gamma and IL-4 in the plasma, and the plasma IFN-gamma/IL-4 ratio, were significantly higher in depressed patients than in controls. The IFN-gamma/TGF-beta1 ratio was also higher in depressed patients, and TGF-beta1 levels showed a significant negative correlation with the HDRS depression scale. After treatment, TGF-beta1 level increased significantly, and the IFN-gamma/IL-4 ratio decreased significantly, in the patient group. However, Th1 changes in male and female showed different trend such as Th1 arm was decreased after the treatment in all male, whereas it was increased in premenopausal age women. LIMITATIONS: Replication and extension using a larger sample size are required. CONCLUSIONS: The Th1 and Th2 cytokine imbalance was observed in subpopulation of depressed patients. TGF-beta1 seemed to play a role in the pathophysiology of depression in this population. Moreover, antidepressant treatment was found to affect the Th1/Th2 balance through the action of TGF-beta1.     

Infectious Th1 and Th2 autoimmunity in diabetes-prone mice

Summary: During terminal maturation of blood monocytes (MO) into macrophages (MAC), a multitude of phenotypic and functional changes occur: cells increase in size and enhance their capacity for phagocytosis and tumor cytotoxicity, but decrease their ability for T-lymphocyte stimulation. The pattern of secreted cytokines is shifted as is the profile of surface antigens. The identity of the MAC maturation-associated antigen MAX.1/ MAX.11 with carboxypeptidase M (CPM), a phosphoinositollinked endopeptidase, was recently described, CPM is able to process a multitude of different substrates, among them immunologically important peptides such as bradykinin, anaphylatoxins and enkephalins. It was previously shown to be expressed in placenta, lung and kidney. CPM as detected by MAX. 1/11 shows a strong expression on MO-derived MAC in vitro and on MAC in vivo accompanying T-lymphocyte activation such as during allogeneic transplant rejection or allergic alveolitis. In contrast, its expression is suppressed on MAC by some types of tumor cells, A synchronous expression of CPM together with MAC cytotoxic function makes a functional relationship very well possible. However, the biological importance of CPM expression on MAC in vivo is difficult to predict, since a wide range of biologically active peptides are substrates for CPM, and the relevance for most of those peptides to be processed by CPM during an immune reaction is only poorly understood at present.     

Nonviable Burkholderia mallei induces a mixed Th1- and Th2-like cytokine response in BALB/c mice

Nonviable cell preparations of Burkholderia mallei, the causative agent of glanders, were evaluated as potential vaccine candidates in a BALB/c murine model. Three different B. mallei cell preparations plus Alhydrogel were evaluated: a heat-killed preparation, an irradiation-inactivated preparation, and a preparation of a capsule-negative mutant strain which had been irradiation inactivated. BALB/c mice were vaccinated twice with the different B. mallei preparations, and spleens and sera were collected to determine their cellular and humoral immune responses. All three bacterial cell preparations had essentially the same results in two cellular immune response assays. In a splenocyte proliferation assay, the amount of cell proliferation in response to the homologous immunogen, concanavalin A, or lipopolysaccharide was similar for all the cell preparations. Also, splenocytes from the inoculated mice expressed interleukin 2 (IL-2), gamma interferon, and small amounts of IL-4 and IL-5, and more IL-10 cytokine in the presence of the homologous antigen. When the immunoglobulin subclasses from these mice were examined, they all produced higher levels of IgG1 than IgG2a subclasses. The higher ratio of IgG1 to IgG2a was not due to the amount of the immunogen or the adjuvant (Alhydrogel) used in the BALB/c mice. The cell preparations did not protect the vaccinated mice from a live challenge (>300 50% lethal doses). Our results suggest that in BALB/c mice, a mixed T-helper-cell-like response to nonviable B. mallei is obtained, as demonstrated by a Th1- and Th2-like cytokine response and a Th2-like subclass immunoglobulin response. This may be the reason for the inability of the B. mallei cells that were examined as candidate vaccines to protect the mice from a live challenge.     

Galectin-1 functions as a Th2 cytokine that selectively induces Th1 apoptosis and promotes Th2 function

Galectin-1 has been implicated in regulating T-cell survival, function, and Th1/Th2 balance in several mouse models, though the molecular and cellular basis of its immuno-modulatory activity has not been completely elucidated. Therefore, we examined galectin-1 expression and activity within differentiated murine Th1 and Th2 subsets. While recombinant galectin-1 specifically bound to both T-cell subsets, Th1 and Th2 T cells expressed distinct combinations of galectin-1-reactive epitopes and were differentially responsive to galectin-1 exposure. Indeed, Th1 cells were more susceptible to galectin-1-induced death than Th2 cells. Th2 protection from apoptosis was correlated with expression of anti-apoptotic galectin-3. Further, galectin-1 promoted TCR-induced type 2 cytokine production by Th2 cells. Differentiated Th2 cells constitutively expressed high levels of galectin-1 and can be induced to produce even higher levels of galectin-1 with restimulation, whereas comparable levels of galectin-1 in Th1 cells were only observed after restimulation. Co-culturing experiments using galectin-1(-/-) and galectin-1+/+ Th1 and Th2 T cells demonstrated that Th2-derived galectin-1 induced Th1 apoptosis, whereas Th1-derived galectin-1 promoted Th2 cytokine production. These studies identify galectin-1 as a cross-regulatory cytokine that selectively antagonizes Th1 survival, while promoting TCR-induced Th2 cytokine production.     

Th1/Th2 cytokine responses following HIV-1 immunization in seronegative volunteers

The Th1/Th2 profile that follows human vaccination may profoundly influence the subsequent course of disease after infection. However, the ability to detect IL-4 has been limited outside trials of live vaccination. By using methods in which memory effector cells are allowed to antigenically expand by short term culture, followed by low-dose mitogenic stimulation, we have been able to follow the Th1/Th2 profile in HIV-1^?volunteers enrolled in two phase I studies of HIV immunogens (a recombinant gp120 and a multivalent, octomeric V3 loop peptide). Antigen-specific interferon-gamma (IFN-γ) could be detected in primary stimulation, but IL-4 was observed only after antigenic expansion and restimulation. In both of these studies the responses after initial immunizations were dominated by IFN-γ, with IL-4 appearing only after multiple rounds of immunization, and IL-4 was temporally related to antibody production. Concomitant with the IL-4 production, the amount of supernatant IFN-γ declined. Antigen-specific IL-10 was not detected in either study. Such techniques, which have been shown to correlate with outcomes in immunotherapy, may prove useful as future surrogates of human vaccine response.     

Cryptococcal infection and Th1-Th2 cytokine balance

Cytokines have been recognized as key factors in determining host resistance to infectious pathogens. In particular, Th1-Th2 cytokine balance in hosts is profoundly associated with the outcome of infection caused by intracellular microbes. In a murine model of pulmonary and disseminated infection with Cryptococcus neoformans, an opportunistic fungal pathogen that frequently leads to fatal meningoencephalitis in severely immunocompromised hosts, expression of cytokine mRNA in the lungs from infected animals revealed Th2-dominant profiles, while administration of IL-12, which rescued mice from fatal infection, converted such balance toward Th1-dominant states in a drastic fashion. Thus, commitment of Th phenotypes critically determines host sensitivity to cryptococcal infection. In this review, we described how Th1-Th2 cytokine balance influences host protective responses to C. neoformans, and we identify the host and pathogen factors that regulate such balance.     

Increased Th1 and Th2 allergen-induced cytokine responses in children with atopic disease

BACKGROUND: Polyclonal cytokine responses following stimulation of T cells with mitogens or superantigens provides information on cytokine production from a wide range of T cells. Alternatively allergen-induced T cell responses can provide information on cytokine production by allergen-reactive T cells. While there is evidence of increased Th2 and reduced Th1 cytokine production following T cell stimulation with non-specific mitogens and superantigens, the evidence that Th1 cytokine production to allergens is decreased in line with a postulated imbalance in Th1/Th2 responses is unclear, with studies finding decreased, no difference or increased IFN-gamma responses to allergens in atopic subjects. OBJECTIVE: To examine childhood polyclonal and allergen-induced cytokine responses in parallel to evaluate cytokine imbalances in childhood atopic disease. METHODS: PBMC cytokine responses were examined in response to a polyclonal stimulus, staphylococcal superantigen (SEB), in parallel with two inhalant allergens, house dust mite (HDM) and rye grass pollen (RYE), and an ingested allergen, ovalbumin (OVA), in (a) 35 healthy children (non-atopic) and (b) 36 children with atopic disease (asthma, eczema and/or rhinitis) (atopic). RESULTS: Atopic children had significantly reduced IFN-gamma and increased IL-4 and IL-5 but not IL13 production to SEB superantigen stimulation when compared with non-atopic children. HDM and RYE allergens stimulated significantly increased IFN-gamma, IL-5 and IL-13, while OVA stimulated significantly increased IFN-gamma production in atopic children. CONCLUSION: We show that a polyclonal stimulus induces a reduced Th1 (IFN-gamma) and increased Th2 (IL-4 and IL-5) cytokine pattern. In contrast, the allergen-induced cytokine responses in atopic children were associated with both increased Th1 (INF-gamma) and Th2 (IL-5 and IL-13) cytokine production. The increased Th1 response to allergen is likely to reflect prior sensitization and indicates that increases in both Th1 and Th2 cytokine production to allergens exists concomitantly with a decreased Th1 response to a polyclonal stimulus in atopic children.     

Th1/Th2相关细胞因子基因检测方法的建立

目的：建立检测Ｔｈ１／Ｔｈ２相关细胞因子的方法。方法：设计６对用于ＩＬ－２、ＩＬ－４、ＩＬ－１０、ＩＬ－１３、ＩＦＮγ和β－ａｃｔｉｎ基因扩增的引物,建立可用于Ｔｈ１／Ｔｈ２相关细胞因子检测的ＲＴ－ＰＣＲ技术,同时 口平移法制备６种细胞因子的ｃＤＮＡ探针,建立ＲＮＡ斑点杂交技术。结果：用ＲＴ－ＰＣＲ和ＲＮＡ斑点杂交技术检测２０种肿瘤细胞株,发现１１／２０为Ｔｈ２型细胞因子表达,８／２０为Ｔｈ０型,     

Th1/Th2相关细胞因子基因检测方法的建立①

目的建立检测Th1/Th2相关细胞因子的方法。方法设计6对用于IL-2、IL-4、IL-10、IL-13、IFNγ和β-actin 基因扩增的引物，建立可用于Th1/Th2相关细胞因子检测的RT-PCR技术，同时用切口平移法制备6种细胞因子的cDNA探针，建立RNA斑点杂交技术。结果用RT-PCR和RNA斑点杂交技术检测20种肿瘤细胞株，发现11/20为Th2型细胞因子表达，8/20为Th0型，1/20未检测到细胞因子。结论RT-PCR技术和RNA斑点杂交技术是检测Th1/Th2相关细胞因子的有效方法。     

细胞因子Th1/Th2偏移与运动及衰老的关系

背景：很多研究都提示机体衰老和疾病过程中均伴有Thl和Th2细胞因子平衡发生偏离的现象。 目的：就运动、衰老和免疫领域的细胞因子与Thl/Th2分化、衰老与Th1/Th2型细胞因子、Th1/Th2型细胞因子平衡在运动延缓衰老中的可能作用方面的研究进行归纳分析。 方法：检索1990/2011PubMed数据及万方数据库有关运动、免疫和衰老等方面的文献,英文检索词为“exercise,immune senescence”,中文检索词为“运动,衰老,免疫”。排除与研究目的无关和内容重复者。保留42篇文献做进一步分析。 结果与结论：随着增龄,老年人易出现T淋巴细胞克隆向Th1亚群分化,进而出现Th1型细胞因子分泌增多,抑制Th2型细胞因子的分泌,破坏了Thl/Th2平衡在机体免疫防御反应的调节中所具有关键性作用,导致糖尿病、肿瘤和自身免疫性疾病等发病率增加。大量研究也证实,运动可以延缓衰老,减少老年性疾病的发生率。是否可以通过Thl/Th2偏移及其偏移的逆转来解释呢？还有待科学实验来予以验证。     

Effect of dietary fat on skin reactivity against histamine, Th1 and Th2 cytokine levels and some serum parameters in mice

Changes in diet may be associated with the increase in allergic disease; change to high-calorie and high-fat diets may be a factor. In this study our objective was to determine skin reactivity of histamine and serum cytokine concentrations in mice fed diets containing different amounts of fat. Histamine reactivity was performed on mice back skin and serum cytokine concentrations were measured by ELISA in mice injected with anti-CD3 antibody. We measured serum interferon-gamma as a Th1-type cytokine and interleukin-4 as a Th2-type cytokine. Mice fed a high fat diet displayed enhanced skin reactivity of histamine and higher IL-4 levels in serum. These data suggest that a high fat diet may play a role in enhancing allergic reactions.     

Human airway and peripheral blood eosinophils enhance Th1 and Th2 cytokine secretion

BACKGROUND: The effector function of eosinophils involves their release of toxic granule proteins, reactive oxygen species, cytokines, and lipid mediators. Murine studies have demonstrated that eosinophils can also enhance T cell function. Whether human eosinophils, in particular, airway eosinophils, have similar immunoregulatory activity has not been fully investigated. The aim of this study was to determine whether human blood and airway eosinophils can contribute to Th1 and Th2 cytokine generation from CD4+ T cells stimulated with superantigen. METHODS: Eosinophils were obtained from blood or bronchoalveolar lavage fluid 48 h after segmental allergen bronchoprovocation. Purified eosinophils were co-cultured with autologous CD4+ blood T cells in the presence of staphylococcal enterotoxin B (SEB). Cytokine levels in the supernatant fluid were determined by enzyme-linked immunosorbent assay (ELISA). Eosinophil expression of major histocompatibility complex (MHC) class II and co-stimulatory molecules was assessed by flow cytometry before culture, 24 h after granulocyte-macrophage colony-stimulating factor (GM-CSF) stimulation, and 24 h after co-culture with CD4+ T cells and SEB. RESULTS: Interleukin (IL)-5, IL-13, and interferon (IFN)-gamma generation increased when CD4+ T cells were co-cultured with either blood or airway eosinophils in the presence of SEB. The ability of eosinophils to enhance cytokine generation was independent of their source (blood vs airway), activation by GM-CSF, or detectable expression of human leukocyte antigen (HLA)-DR, CD80, or CD86. CONCLUSION: Our data demonstrate that SEB-induced generation of Th1 and Th2 cytokines is increased in the presence of human blood and airway eosinophils. Thus, eosinophils can have an immunoregulatory function in pathogen-associated allergic diseases such as atopic dermatitis, chronic sinusitis, and asthma exacerbations.     

Th1/Th2 cytokine gene polymorphisms in patients with idiopathic pulmonary fibrosis

We investigated 30 patients with idiopathic pulmonary fibrosis (IPF) and 103 healthy volunteers for the cytokines polymorphisms of the IL-1alpha, IL-1beta, IL-1R, IL-1RA, IL-2, IL-4, IL-6, IL-10, IL-12, tumor necrosis factor-alpha, interferon-gamma, transforming growth factor-beta, IL-1beta, IL-2, IL-4, and IL-4RA genes. The strongest correlation of a genotype with the disease was found for gene polymorphisms at the promotor region of IL-4, where the CT genotypes at the positions (-590) and (-33) were more frequent in the IPF group (P < 0.0001, P(corr) < 0.0022; vs P < 0.0001, P(corr) < 0.0022). Our results support the idea of the pathogenic role of cytokine gene polymorphisms in the etiology and pathogenesis of IPF, with emphasize on the IL-4 promotor gene polymorphisms.     

Th1 and Th2 cytokine secretion patterns in murine candidiasis: association of Th1 responses with acquired resistance.

Two chemically mutagenized agerminative variants of Candida albicans were used to immunize mice against challenge with highly virulent cells of the parent strain. Although both mutants (Vir- 3 and Vir- 13) resulted in nonlethal infection and could be recovered from mouse organs for many days after the intravenous inoculation of 10(7) to 10(6) cells, significant protection to systemic challenge with virulent C. albicans was induced by only one (Vir- 3) of the two variants. Anticandidal resistance in Vir- 3-infected mice was associated with the occurrence in vivo of strong delayed-type hypersensitivity to Candida antigen, detection in vitro of highly fungicidal effector macrophages, and presence in the serum of a large proportion of Candida-reactive antibodies of the immunoglobulin G2a isotype. Bulk cultures of purified CD4+ lymphocytes from mice infected with either mutant were compared for their ability to produce gamma interferon (IFN-gamma), interleukin-2 (IL-2), IL-4, and IL-6 in vitro. After stimulation with specific antigen, CD4+ cells from Vir- 3-immunized mice released large amounts of the Th1-specific cytokines, IFN-gamma and IL-2, at a time when CD4+ cells from Vir- 13-infected mice predominantly secreted the characteristic Th2 cytokines, IL-4 and IL-6. These results were confirmed by quantitative analysis of cytokine-producing Th1 and Th2 cells. In addition, only mice infected with Vir- 3 displayed a high frequency of CD8+ cells with the potential for in vitro lysis of yeast-primed bone marrow macrophages. Purified CD4+ cells from Vir- 3-infected mice, but not a mixture of these cells with CD4+ lymphocytes from mice infected with Vir- 13, could adoptively transfer delayed-type hypersensitivity reactivity onto naive mice. Taken together, these data suggest that both Th1 and Th2 CD4+ lymphocytes may be activated during experimental C. albicans infection in mice.