Development of Spontaneous Airway Changes Consistent with Human Asthma in Mice Lacking T-bet

Finotto, Susetta; Neurath, Markus F.; Glickman, Jonathan N.; Qin, Shixin; Lehr, Hans A.; Green, Francis H. Y.; Ackerman, Kate G.; Haley, Kathleen J.; Galle, Peter R.; Szabo, Susanne J.; Drazen, Jeffrey M.; Sanctis, George T. De; Glimcher, Laurie H.

doi:10.1126/science.1065544

Cited by 552 publications

(452 citation statements)

References 15 publications

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“…One possible explanation is that there is immune deviation in asthma toward T-helper 2 (Th2) predominance, with elevated IL-4, IL-5 and IL-13, which might inhibit Th1 responses that could protect against cancer. 24,25 This skewing of the immune response toward the Th2 phenotype could exacerbate the effects of the pesticides, which may partly act as carcinogens, and may also inhibit the immune response, acting synergistically with the asthma. Some pesticides might also inhibit a different arm of the immune response, e.g., cytotoxic T lymphocytes or natural killer (NK) cells, 26,27 so that the combination of asthma and pesticides exposure eliminates more than one mechanism of immunosurveillance.…”

Section: Resultsmentioning

confidence: 99%

Non‐Hodgkin's lymphoma among asthmatics exposed to pesticides

Lee

Cantor

Berzofsky

et al. 2004

Intl Journal of Cancer

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We conducted a pooled analysis of population-based casecontrol studies in Iowa, Minnesota and Nebraska to investigate whether asthma modifies risk of non-Hodgkin's lymphoma (NHL) associated with pesticide exposures. Cases (n ‫؍‬ 872) diagnosed with NHL from 1980 to 1986 and frequency-matched controls (n ‫؍‬ 2,381) randomly selected from the same geographic areas as the cases were included. Information on use of pesticides and history of asthma was based on interviews. Unconditional logistic regression was used to calculate ORs, adjusted for age, state and vital status. Of all subjects, 177 (45 cases, 132 controls) reported having been told by their doctor that they had asthma. Subjects with an asthma history had a nonsignificantly lower risk of NHL than nonasthmatics (OR ‫؍‬ 0.6, 95% CI 0.3-1.4), and there was no main effect of pesticide exposure (OR ‫؍‬ 1.0, 95% CI 0.8 -1.2). However, asthmatics tended to have larger ORs associated with exposure to pesticides than nonasthmatics. The OR among asthmatics was 1.8 (95% CI 1.1-3.2) for everuse of crop insecticides, 2.7 (95% CI 1.0 -7.2) for chlordane, 2.4 (95% CI 1.0 -5.7) for lindane and 3.7 (95% CI 1.3-10.9) for fonofos. Among nonasthmatics, ORs were 1.1 (0.9 -1.3), 1. Incidence and mortality rates for non-Hodgkin's lymphoma (NHL) have been increasing worldwide over the past several decades. 1 Although the reasons for this increase are not fully understood, NHL is known to be associated with a compromised immune system, particularly acquired or genetic immunodeficiencies. 2,3 Medical conditions related to more subtle immune alteration, such as asthma and other allergic conditions, have also been studied as potential risk factors for NHL. 4 -10 These reports have described a decreased risk for NHL among persons with a history of asthma or allergies, 4,5 no association 6 -8 or an increase in risk. 9,10 Exposure to pesticides has also been suggested as a possible risk factor for NHL. [11][12][13][14][15] Pesticides may increase cancer risk by altering the immune system. 16 -19 Because both asthma and pesticide exposure may change the risk of NHL by immunologic alterations, we investigated the relation between pesticide exposure, asthma and risk of NHL. MATERIAL AND METHODS Study populationWe pooled data from 2 population-based case-control studies of NHL in 3 midwestern states in the United States, which have been described in detail previously. 20,21 In Iowa and Minnesota, all newly diagnosed cases of NHL among white men aged Ն30 were ascertained from records of the Iowa State Health Registry and a special surveillance system of Minnesota hospitals and pathology laboratories from 1980 to 1983 (n ϭ 530). In Nebraska, all cases of NHL diagnosed between July 1983 and June 1986 among white men and women aged Ն21 in 45 eastern counties were identified through the Nebraska Lymphoma Study Group and area hospitals (n ϭ 346). All cases were reviewed by pathologists, and only histologically confirmed cases were included in this analysis. Controls were randomly selected from ...

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Section: Resultsmentioning

confidence: 99%

Non‐Hodgkin's lymphoma among asthmatics exposed to pesticides

Lee

Cantor

Berzofsky

et al. 2004

Intl Journal of Cancer

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“…Given its critical role, it is not surprising that abnormal T-bet expression can be associated with diseases characterized by imbalance between Th1-Th2 or aberrant IFN-c gene expression. In fact, T-bet itself may be a target of Leishmania major infection, lymphocytic choriomeningitis virus infection, insulin-dependent diabetes, inflammatory bowel disease, experimental allergic encephalomyelitis, and asthma [3,[10][11][12][13][14].…”

Section: Discussionmentioning

confidence: 99%

“…In addition, T-bet is required by dendritic cells for the optimal production of IFN-c and for full activation of antigen-specific Th1 cells [9]. Experiments in T-bet -/-mice support its importance in control of Leishmania major infection, lymphocytic choriomeningitis virus infection, insulin dependent diabetes, inflammatory bowel disease, experimental allergic encephalomyelitis, asthma and other Th1-mediated diseases [3,[10][11][12][13][14].…”

Section: Introductionmentioning

confidence: 96%

Transcriptional control of human T‐BET expression: The role of Sp1

Min

Boyd

et al. 2007

Eur J Immunol

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Murine T-bet (T-box expressed in T cells) is a master regulator of IFN-c gene expressionin NK and T cells. T-bet also plays a critical role in autoimmunity, asthma and other diseases. However, cis elements or trans factors responsible for regulating T-bet expression remain largely unknown. Here, we report on our discovery of six Sp1-binding sites within the proximal human T-BET promoter that are highly conserved among mammalian species. Electrophoretic mobility shift assays demonstrate a physical association between Sp1 and the proximal T-BET promoter with a direct dose response between Sp1 expression and T-BET promoter activity. Ectopic overexpression of Sp1 also enhanced T-BET expression and cytokine-induced IFN-c secretion in NK cells and T cells. Mithramycin A, which blocks the binding of Sp1 to the T-BET promoter, diminished both T-BET expression and IFN-c protein production in monokine-stimulated primary human NK cells. Collectively, our results suggest that Sp1 is a positive transcriptional regulator of T-BET. As T-BET and IFN-c are critically important in inflammation, infection, and cancer, targeting Sp1, possibly with mithramycin A, may be useful for preventing and/ or treating diseases associated with aberrant T-BET or IFN-c expression.

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“…1,2 T-bet belongs to a family of transcription factors, the members of which share a highly conserved DNA-binding domain T-box, flanked by diverse non-DNA-binding domains, which are involved in transactivation or repression. [3][4][5][6] A series of studies in vitro and in vivo showed that T-bet is induced by the T-cell receptor and the IFN-gR/STAT1 signaling pathway in antigen-recognizing naive CD4 þ T cells. The elevated T-bet induces IL-12Rb2 and IFN-g expression, allowing IL-12R/STAT4 signaling to optimize IFN-g expression, and thereby amplifying and establishing the effector commitment of Th1 cells.…”

Section: Introductionmentioning

confidence: 99%

Onecut transcription factor OC2 is a direct target of T-bet in type-1 T-helper cells

et al. 2008

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T-box transcription factor, T-bet, has a central role in the differentiation of T-helper (Th) progenitor cells to Th1 or Th2 effector cells, partly by regulating the expression of genes such as interferon-g (IFN-g). However, the direct target genes, especially those mediating the transcriptional network initiated by T-bet, are not yet fully understood. By combining chromatin immunoprecipitation from Th1 cells with human cytosine-phosphate-guanine-island array analysis, Onecut 2 (OC2), which encodes a member of the ONECUT class of transcriptional activators, was identified as a direct target gene of T-bet. OC2 is expressed in Th1 but not Th2 cells and reporter assays showed that T-bet transactivates OC2 transcription through putative T-bet half-sites locating À451 to À347 of OC2 promoter region. Moreover, we found that OC2 binds and transactivates human T-bet promoter. These results suggest that not only cell-extrinsic regulation via the IFN-g/STAT1 pathway, but also cell-intrinsic transcriptional positive feedback loop between T-bet and OC2 could be involved in Th1 development.

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Development of Spontaneous Airway Changes Consistent with Human Asthma in Mice Lacking T-bet

Cited by 552 publications

References 15 publications

Non‐Hodgkin's lymphoma among asthmatics exposed to pesticides

Non‐Hodgkin's lymphoma among asthmatics exposed to pesticides

Transcriptional control of human T‐BET expression: The role of Sp1

Onecut transcription factor OC2 is a direct target of T-bet in type-1 T-helper cells

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