Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P15088 (mast cell)
 14,925 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cytokines represent the major factors involved in the communication between T cells, macrophages and other immune cells in the course of an immune response to antigens and infectious agents. A number of studies on mouse and human T helper (Th) clones have recently provided extensive evidence for the existence of different activities exhibited by Th cells (called Th1 and Th2), which was apparently inferred from the profile of cytokine secretion. The Th1-type immune response is generally associated with IgG2a production and the development of cellular immunity, the Th2-type response with IgE production, eosinophils and mast cell production. This review focuses on the role of different cytokines produced by macrophages (especially interferons (IFNs), TNF-alpha, IL-10 and IL-12) or T cells (IFNs, IL-2, IL-4, IL-10, IL-13 and TGF-beta) in macrophage-T cell interactions and the cytokine relevance in the differentiation of Th cells towards the Th1 or Th2 type of immune response. Th1-derived cytokines (IFN-gamma, IL-2, TNF-alpha) favor macrophage activation, whereas the Th2 cytokines (IL-4, IL-10, IL-13) exhibit suppressive activities on macrophage functions. A key role in the differentiation towards the Th1-type response is now attributed to IL-12, a recently described cytokine produced mainly by macrophages. Its production can be upregulated by IFN-gamma and is inhibited by IL-10 and IL-4. All this emphasizes the importance of macrophage-cytokine interactions in determining the type of immune response. This article also aims to review recent data concerning the roles of IFNs alpha/beta (type I) and IFN-gamma (type II) in the regulation of the immune response. While there is much information on the regulatory effects of IFN-gamma (also called "immune IFN") on the immune response, little is so far known of the role of type I IFNs. These cytokines, originally described as simple antiviral substances, are now taken to be important regulators of the immune response. Recent data indicate that these molecules (especially IFNs-alpha) specifically promote the differentiation towards the Th1-type response. The stimulatory effects of IFN-alpha on the generation of the Th1-type response may be involved in its therapeutic effects in some human diseases, including early AIDS, hypereosinophilia and certain tumors.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Role of interferons and other cytokines in the regulation of the immune response. 753 71

Myelin basic protein (MBP)-specific SJL/J T cells were cultured in normal growth medium or growth medium supplemented with 10% culture supernatant from WEHI-3 cells, a source of interleukin-3 (IL-3), or with recombinant IL-3. T cell lines cultured with IL-3 supplementation were more encephalitogenic compared to parallel lines cultured without this supplement. There was little difference in antigen-specific proliferative response or expression of cell surface markers CD3, CD4, CD8, IL-2R, or alpha/beta TCR in the parallel lines. Supernatant fluids from antigen-stimulated T cells from each cycle were tested for the presence of IL-2, IL-3, IL-4, granulocyte macrophage colony-stimulating factor (GM-CSF), tumor necrosis factor-alpha (TNF alpha/beta) and transforming growth factor-beta (TGF beta). No significant difference in IL-2, IL-4, GM-CSF, TNF alpha/beta, or TGF beta levels were seen when supplemented and unsupplemented cultures were compared. Supernatant culture fluids contained an activity that was highly stimulatory for the IL-3-dependent mouse mast cell line, MC/9. This activity was attributable to a combination of at least three factors that varied in relative concentrations throughout the course of the experiments. Based on neutralization by monoclonal antibodies, MC/9 stimulating activity in early passage lines was attributable entirely to IL-3 and GM-CSF. The fraction of the MC/9 stimulatory activity that could be neutralized by monoclonal antibody to IL-3 decreased with increasing stimulation cycle while the fraction neutralized by anti-GM-CSF antibodies remained relatively constant. At the time that the lines lost encephalitogenicity, the activity neutralizable by anti-IL-3 had dropped to low levels in the culture supernatants; however, MC/9 stimulatory activity remained present in the supernatants. This was due to GM-CSF and a third unidentified factor.
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PMID:Interleukin-3 and encephalitogenic activity of SJL/J myelin basic protein-specific T cell lines. 768 50

The discovery of anaphylaxis by Portier and Richet that reinjection of a substance caused disease instead of immunity was sensational as it was against the prevailing DOGMA. Passive transmission of hypersensitivity with human antibody by Prausnitz (the P-K reaction, 1921) was an important step in the study of human hypersensitivity. Anaphylaxis was shown to be the consequence of liberation of vasoactive substances (histamine and SRS-A) from mast cells when the allergen crosslinks two IgE molecules fixed to mast cell Ig receptors (Ovary, 1961). The use of smooth muscle contraction (Dale, 1913) and vascular permeability increase (PCA, Ovary, 1948) became important for experimental studies. The clonal selection of antibody formation (Burnet, 1929) opened a new era in immunological concepts. The demonstration of the Fc receptor on mast cells (Ovary, 1961) called attention to the importance of cellular receptors. The carrier effect (Ovary & Benacerraf, 1963) was explained by recognition by T cell receptors of a processed carrier fragment complexed to Ia molecules (Unanue, Grey, 1981). Human IgE responsible for allergies was discovered in 1965 by K. & T. Ishizaka. Tonegawa in 1973 destroyed the "one gene-one protein" DOGMA, showing that the immunoglobulin, germline gene is discontinuous: i.e., composed of exons (which will form the Ig molecule) separated by introns. The CD4 cells were subdivided into Th1 and Th2 cells (Mosmann & Coffman, late 1980's). The Th2 secretes IL-4 necessary for IgE production (Paul, Vitetta, & others, early 1980's). B cells multiply before antibody production or become memory B cells, but what causes a B cell to become a memory cell is not known. The B cell does not change specificity but can switch the isotype using "switch recombinase" and the s segment of the Ig molecules (Honjo, early 1980's). IgE production was shown to be suppressed by lymphokines, such as IFN-gamma and IL-2. A great progress in understanding the mechanism of allergic reaction has been the result of intense investigations by many scientists. A more complete understanding, better prophylaxis and an improved treatment are the goals of the near future.
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PMID:Immediate hypersensitivity. A brief, personal history. 769 78

Interleukin 9 (IL-9) is a TH2 cytokine that has been shown to promote the antigen-independent growth of some mouse T helper clones. To characterize the specificity of IL-9-mediated T cell activation, we used a murine T cell clone that could grow with either IL-9 or IL-2. After differential hybridization of a cDNA library, we isolated three genes that were expressed preferentially in the presence of IL-9. Two of them correspond respectively to granzyme A and granzyme B, two proteases expressed by activated T cells. By Northern blot hybridization and functional assays, we found that IL-9 induced the expression of granzyme B in several T cell clones as well as in mast cell lines. In addition, other proteases such as the mouse mast cell proteases were also found to be expressed by IL-9-activated T cell clones. The third IL-9-induced cDNA corresponds to the alpha-chain of the high-affinity receptor for IgE. Several T cell clones expressed this IgE receptor mRNA and were able to bind IgE with high affinity. Taken together, our results indicate that IL-9 induces a mast cell-like phenotype in T cell clones.
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PMID:IL-9 induces expression of granzymes and high-affinity IgE receptor in murine T helper clones. 773 Jun 12

We analysed the cytokine profile of a T cell subset (CD4+ CD45 RC-) that confers protection against Trichinella spiralis infection in rats. These CD4+ cells are generated in the gut and appear in the thoracic duct lymph within 72 h after infection. Cytokine mRNA levels for IL-2, IL-3, IL-4, IL-5, IL-10 and IFN-gamma and functional cytokine secretion for IL-4, IL-5, IFN-gamma, TNF-alpha and mast cell differentiation activity were tested in vitro following stimulation with T. spiralis antigens. Compared to a non-protective T cell population (CD4+ CD45 RC+ or CD8+), also isolated from the same thoracic lymph, no significant differences were observed in the levels of mRNA for IL-2, IL-3, IL-4, IL-5, IL-10 or IFN-gamma in the protective CD4+ CD45 RC- cells. However, analysis of the cytokine activities in culture supernatant of these T cell subsets following 24 h stimulation in vitro with T. spiralis antigens showed that significant IL-4 and IL-5 activity but little IFN-gamma or TNF-alpha was secreted by the protective CD4+ CD45- RC- cells. Whereas the non-protective CD4+ CD45 RC+ cells secreted significant levels of IL-4, IFN-gamma, mast cell differentiating activity and TNF-alpha but little IL-5 activity. Non-protective CD8+ cells were found to secrete IL-4 but not IL-5. Production of IL-4 was essentially equal for both protective and non-protective T cell subsets. These findings suggest that the presence or absence of IFN-gamma secretion, rather than IL-4 alone, determines whether a T cell subset has protective activity against T. spiralis infection in rats.
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PMID:Cytokine profile of protective anti-Trichinella spiralis CD4+ OX22- and non-protective CD4+ OX22+ thoracic duct cells in rats: secretion of IL-4 alone does not determine protective capacity. 780 64

While LCF is present in BAL early after antigen challenge, we know little about its other potential effects beyond CD4+ T cell, monocyte, and eosinophil chemotaxis and monocyte and CD4+ T cell activation. The work described here focuses on the hypothesis that the secreted protein products of T cells participate in the airway inflammatory process that underlies human asthma, and in particular that LCF could play an early role because of the unusual responsiveness of LCF-producing T to histamine. To date, most studies have addressed the measurement of cytokines derived from CD4+ T cells (e.g., IL-2, IL-3, IL-4, IL-5, and GM-CSF) in the airways of asthmatics, and attempted to correlate the presence of protein or mRNA with the complexion of the inflammatory infiltrate. These studies have been based upon the reports that there are increased numbers of CD4+ T cells in the airways of asthmatics, and that the presence of eosinophils might correlate with the secretion of TH2-type cytokines like IL-3, -4, and -5. Using this information as a background, our work has approached the problem in an entirely different way. We have focused our attention on the early events in antigen-induced asthma that are responsible for CD4+ cell accumulation in the lung, including CD4+ T cells, eosinophils, and monocytes. We have attempted to identify mechanisms by which mast cell mediators, in particular histamine, might play a role in the secretion of chemotactic lymphokines that are selective for CD4+ cells by using CD4 itself as a chemotactic factor receptor.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Cytokine binding to CD4+ inflammatory cells: implications for asthma. 795 94

Mast cell synovial hyperplasia can occur in patients with rheumatoid arthritis. Histamine can accelerate synovitis and heparin can inhibit lymphocyte function. Since interleukin-4 (IL-4) can stimulate murine mast cell and IgE synthesis, we determined whether mast cell mediators and anti-IL-4 might effect lymphocyte proliferation from patients with rheumatoid arthritis. Twenty-four patients with rheumatoid arthritis and nine normal controls were evaluated by history, physical examination, physician and patient-assessed joint and allergic symptoms, and diary scores. An IL-2-driven-T cell (3H) Tdr proliferation assay with monoclonal anti-IL-4 and a sensitive ELISA were performed with isolated peripheral blood mononuclear cells (PBMC) with 10 micrograms/mL of either concanavalin A (Con A), type I human collagen, or heparin and 10(-6) M histamine. Increased lymphocyte proliferation indices with Con A (mean 21.69 +/- 4.9; 6.54 +/- 3.2 normal controls), type I human collagen (mean 2.17 +/- 0.52; 1.1 +/- .17, normal controls), histamine (mean 1.66 +/- .36; 0.62 +/- 0.08, normal controls), heparin (mean 1.61 +/- .38; 0.69 +/- .11, normal controls) occurred in peripheral blood mononuclear cells from all patients with rheumatoid arthritis compared with normal controls (P < .0236 to .0015) which was inhibited in 32% of peripheral blood mononuclear cells by anti-IL-4. Increased IL-4 ELISA levels in cultured supernatants were noted with heparin (P < .25) and collagen (P < .05).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Increased interleukin-4 production in response to mast cell mediators and human type I collagen in patients with rheumatoid arthritis. 815 36

Cytokine-activation pathways in mast cells are supposed to play a significant role in host defense mechanisms and allergic reactions. Interleukin-4 (IL-4) is a well-characterized regulator of growth and function of mast cells. The human mast cell line HMC-1 was established from a patient suffering from mast cell leukemia and was shown to expose IL-4 binding sites. In the present study, the effects of recombinant human (rh) IL-4 and other rh cytokines (IL-2, IL-3, IL-6, IL-8) on expression of cytokine mRNA in HMC-1 cells were examined by Northern blot analysis using oligonucleotide probes. Tumor necrosis factor alpha (TNF-alpha) and IL-1 beta transcripts were found to be expressed constitutively in HMC-1 cells, whereas transcripts for IL-3, IL-4, IL-5, IL-6, and granulocyte-macrophage colony-stimulating factor (GM-CSF) could not be detected. Of all cytokines tested, rhIL-4 was found to down-regulate IL-1 beta mRNA expression and formation of immunoreactive IL-1 beta protein in HMC-1 cells. The effect of IL-4 on IL-1 beta gene product expression was time- and dose-dependent (maximum effects obtained with 100 U/mL of rhIL-4). No effect of IL-4 on expression of TNF-alpha mRNA in HMC-1 cells was observed. These results raise the possibility that human mast cells are a source of both TNF-alpha and IL-1 beta. Furthermore, our study provides evidence that IL-4 regulates IL-1 beta gene product expression in HMC-1 cells. The HMC-1 cell line should be a useful tool for studying cytokine activation pathways in human mast cells.
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PMID:Tumor necrosis factor alpha and interleukin-1 beta mRNA expression in HMC-1 cells: differential regulation of gene product expression by recombinant interleukin-4. 833 Jun 51

In contrast to most cytokines, interleukin 4 (IL-4) expression is restricted to T lymphocytes, with the exception of mast cell lines and mast cells, as more recently demonstrated in rodents. Little is known, however, about the capacity of human nonlymphoid cells to produce IL-4. In this study we show that mature human basophils are capable of expressing IL-4 and examine the regulation of IL-4 production in comparison with the lipid mediator leukotriene C4. IL-4 was produced upon immunoglobulin E receptor (IgER) activation of basophils cultured with IL-3, a cytokine previously shown to prime these cells for enhanced release of inflammatory mediators. In some experiments, IL-3 or IgER activation alone also induced IL-4 production close to the detection limit. The effect of IL-3 on IgER-dependent IL-4 expression was dose and time dependent: maximal IL-4 production occurred between 18 and 48 h preexposure of basophils to 3-10 ng/ml IL-3. IgER-induced IL-4 synthesis and release by basophils cultured with IL-3 was rapid and complete after 6 h. In contrast to IL-3, other cytokines (IL-5, granulocyte/macrophage colony-stimulating factor, and nerve growth factor) that also prime basophils for enhanced histamine and leukotriene C4 release did not promote IgER-induced IL-4 synthesis. Basophils appear to secrete a "TH2-like" cytokine profile since no detectable IL-2 or interferon gamma was produced upon IgER activation. Mononuclear cells (depleted of basophils), cultured in parallel, did not release IL-4 in response to IL-3 and/or IgER activation, and produced approximately ten times less IL-4 than basophils upon nonspecific activation by phorbol ester and calcium ionophore. Thus, human basophils are an important cellular source of IL-4, and may, therefore, in addition to their inflammatory effector functions, also regulate the differentiation of T helper cells and B cells, in particular in allergic diseases.
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PMID:Human peripheral blood basophils primed by interleukin 3 (IL-3) produce IL-4 in response to immunoglobulin E receptor stimulation. 843 4

Human mast cells readily release a variety of mediators, including cytokines, in response to IgE receptor crosslinking, but the mechanisms governing the expression of cytokines are still unclear. Using a human mast cell line, HMC-1, we show expression of cytokine transcripts as early as 2 h after activation with ionomycin and phorbol myristate acetate (PMA). Resting HMC-1 cells expressed transcripts for interleukin-1 receptor antagonist (IL-1RA), IL-2, IL-4, IL-5, GM-CSF, and weakly for IL-8, and stimulation with ionomycin and PMA induced additional transcripts for IL-6 and IL-13 and upregulated expression of IL-8 transcripts. HMC-1 cells secreted IL-4, IL-8, and GM-CSF protein after activation and dexamethasone significantly inhibited the production of these cytokines. Of significance is the finding that the addition of membranes purified from activated T cells to mast cell cultures induced transcripts selectively for IL-8 and none for other proinflammatory cytokines. Flow cytometry revealed that resting HMC-1 cells express CD40, a molecule involved in contact-dependent signaling of monocytes and B cells by T cells. However, activation of HMC-1 by anti-CD40 antibody did not induce IL-8 gene expression or protein production. This study demonstrates that human mast cells are capable of expressing multiple cytokines that can be inhibited by glucocorticoids. It also raises the possibility that T cells may activate mast cell cytokine synthesis by novel contact-dependent mechanisms. This phenomenon of T cell regulation of mast cell function requires further study.
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PMID:Multifunctional cytokine expression by human mast cells: regulation by T cell membrane contact and glucocorticoids. 908 42


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