scholarly journals Interleukin-4 and Transforming Growth Factor β Have Opposing Regulatory Effects on Gamma Interferon-Mediated Inhibition of Cryptosporidium parvum Reproduction

2003 ◽  
Vol 71 (8) ◽  
pp. 4580-4585 ◽  
Author(s):  
I.-Sarah Lean ◽  
Stuart A. C. McDonald ◽  
Mona Bajaj-Elliott ◽  
Richard C. G. Pollok ◽  
Michael J. G. Farthing ◽  
...  
Keyword(s):  
Growth Factor ◽  
Cryptosporidium Parvum ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Inhibitory Effect ◽  
Gamma Interferon ◽  
Interleukin 4 ◽  
Effector Cells ◽  
Ifn Γ

ABSTRACT It was shown previously that enterocytes activated by gamma interferon (IFN-γ) are efficient effector cells in the killing of Cryptosporidium parvum. How this function is regulated is not clearly understood, but transforming growth factor β (TGF-β) and the Th2 regulatory cytokines may play a role. Using an in vitro cell culture system, we investigated how the key regulatory cytokines interleukin-4 (IL-4), IL-10, IL-13, and TGF-β might modulate the effect of IFN-γ in inducing resistance to infection in enterocyte cell lines. The results showed that TGF-β can abolish the inhibitory effect on C. parvum development and that neither IL-13 nor IL-10 influenced the action of IFN-γ. In contrast, IL-4 cooperated with low concentrations of IFN-γ (1 and 10 U/ml) to enhance parasite killing. One mechanism that appeared to be involved in the combined activity of IFN-γ and IL-4 was intracellular Fe2+ deprivation, but induction of nitric oxide production was not involved. In one cell line, the extents and durations of phosphorylation of STAT1, a transcription factor involved in IFN-γ signaling, were similar when cells were stimulated with IFN-γ alone and with IFN-γ and IL-4γ, suggesting that the cooperative effect of the cytokines was not related to STAT1 activation. The effects of the presence of TGF-β and IL-4 on IFN-γ function did not appear to involve any alteration in the level of expression of IFN-γ receptors.

scholarly journals Effects of Gamma Interferon, Interleukin-10, and Transforming Growth Factor β on the Survival of Mycobacterium avium subsp. paratuberculosis in Monocyte-Derived Macrophages from Naturally Infected Cattle

2004 ◽  
Vol 72 (4) ◽  
pp. 1974-1982 ◽  
Author(s):  
M. S. Khalifeh ◽  
J. R. Stabel
Keyword(s):  
Growth Factor ◽  
Cell Cultures ◽  
Mycobacterium Avium ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Interleukin 10 ◽  
Gamma Interferon ◽  
Ifn Γ ◽  
Culture Supernatants

ABSTRACT Gamma interferon (IFN-γ) plays a significant role in the control of mycobacterial infections, including Mycobacterium avium subsp. paratuberculosis. However, the contribution of other immunoregulatory cytokines, such as interleukin-10 (IL-10) and transforming growth factor β (TGF-β), in Johne's disease has not been investigated as yet. In this study, we examined the effects of in vivo and in vitro infection with M. avium subsp. paratuberculosis on the production of IFN-γ, IL-10, and TGF-β by peripheral blood mononuclear cells (PBMC). We also examined the effects of exogenous IFN-γ, IL-10, and TGF-β on M. avium subsp. paratuberculosis survival in the cell cultures. PBMC obtained from naturally infected cows, regardless of their disease status, specifically upregulated IL-10 and TGF-β in culture supernatants in response to stimulation with live M. avium subsp. paratuberculosis. Nonstimulated PBMC recovered from subclinically infected animals secreted the lowest levels of TGF-β, but after stimulation with live M. avium subsp. paratuberculosis, TGF-β levels in the culture supernatants increased to levels similar to that produced by PBMC from healthy animals. The numbers of viable M. avium subsp. paratuberculosis recovered from cultures from naturally infected animals were higher than those from healthy cows after in vitro infection with M. avium subsp. paratuberculosis. The addition of exogenous IL-10 and TGF-β to PBMC isolated from healthy cows inhibited the bactericidal activity of these cells as evidenced by the increased number of viable M. avium subsp. paratuberculosis recovered from these cultures compared to cell cultures containing medium alone. These data suggest important immune regulatory roles for IL-10 and TGF-β during infection with M. avium subsp. paratuberculosis that may be directly related to their effects on macrophage activation and killing of M. avium subsp. paratuberculosis.

scholarly journals Differential Expression of Interleukin-4 (IL-4) and IL-4δ2 mRNA, but Not Transforming Growth Factor Beta (TGF-β), TGF-βRII, Foxp3, Gamma Interferon, T-bet, or GATA-3 mRNA, in Patients with Fast and Slow Responses to Antituberculosis Treatment

2008 ◽  
Vol 15 (8) ◽  
pp. 1165-1170 ◽  
Author(s):  
Joel Fleury Djoba Siawaya ◽  
Nchinya Bennedict Bapela ◽  
Katharina Ronacher ◽  
Nulda Beyers ◽  
Paul van Helden ◽  
...  
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Early Stage ◽  
Gamma Interferon ◽  
Sputum Culture ◽  
Interleukin 4 ◽  
Antituberculosis Treatment ◽  
Ifn Γ ◽  
Growth Factor Beta

ABSTRACT This study investigated interleukin-4 (IL-4), IL-4δ2, transforming growth factor beta (TGF-β), TGF-βRII, Foxp3, GATA-3, T-bet, and gamma interferon (IFN-γ) transcription in peripheral blood samples of adult pulmonary tuberculosis patients prior to and after 1 week of therapy. Twenty patients with positive results for sputum culture for Mycobacterium tuberculosis were enrolled and treated with directly observed short-course antituberculosis chemotherapy. Early treatment response was assessed. At the end of the intensive phase of treatment (month 2), 12 patients remained sputum culture positive (slow responders) and 8 converted to a negative culture (fast responders). Only the expression levels of IL-4 (4-fold decrease) and IL-4δ2 (32-fold increase) changed significantly during the first week of therapy in the 20 patients. No baseline differences were present between the responder groups, but fast responders had significantly higher IL-4 transcripts than slow responders at week 1. Fast responders showed a 19-fold upregulation and slow responders a 47-fold upregulation of IL-4δ2 at week 1. Only slow responders also showed a significant decrease in IL-4 expression at week 1. There were no significant differences in expression of TGF-β, TGF-βRII, Foxp3, IFN-γ, and GATA-3 between the groups. These data show that differential IL-4-related gene expression in the early stage of antituberculosis treatment accompanies differential treatment responses and may hold promise as a marker for treatment effect.

scholarly journals Medulloblastoma rendered susceptible to NK-cell attack by TGFβ neutralization

2019 ◽  
Vol 17 (1) ◽  
Author(s):  
Allison B. Powell ◽  
Sridevi Yadavilli ◽  
Devin Saunders ◽  
Stacey Van Pelt ◽  
Elizabeth Chorvinsky ◽  
...  
Keyword(s):  
Nk Cells ◽  
Transforming Growth Factor ◽  
Nk Cell ◽  
Transforming Growth Factor Β ◽  
In Vitro Models ◽  
Dominant Negative ◽  
Conditioned Media ◽  
Retroviral Transduction ◽  
Effector Cells

Abstract Background Medulloblastoma (MB), the most common pediatric brain cancer, presents with a poor prognosis in a subset of patients with high risk disease, or at recurrence, where current therapies are ineffective. Cord blood (CB) natural killer (NK) cells may be promising off-the-shelf effector cells for immunotherapy due to their recognition of malignant cells without the need for a known target, ready availability from multiple banks, and their potential to expand exponentially. However, they are currently limited by immune suppressive cytokines secreted in the MB tumor microenvironment including Transforming Growth Factor β (TGF-β). Here, we address this challenge in in vitro models of MB. Methods CB-derived NK cells were modified to express a dominant negative TGF-β receptor II (DNRII) using retroviral transduction. The ability of transduced CB cells to maintain function in the presence of medulloblastoma-conditioned media was then assessed. Results We observed that the cytotoxic ability of nontransduced CB-NK cells was reduced in the presence of TGF-β-rich, medulloblastoma-conditioned media (21.21 ± 1.19% killing at E:T 5:1 in the absence vs. 14.98 ± 2.11% in the presence of medulloblastoma-conditioned media, n = 8, p = 0.02), but was unaffected in CB-derived DNRII-transduced NK cells (21.11 ± 1.84% killing at E:T 5:1 in the absence vs. 21.81 ± 3.37 in the presence of medulloblastoma-conditioned media, n = 8, p = 0.85. We also observed decreased expression of CCR2 in untransduced NK cells (mean CCR2 MFI 826 ± 117 in untransduced NK + MB supernatant from mean CCR2 MFI 1639.29 ± 215 in no MB supernatant, n = 7, p = 0.0156), but not in the transduced cells. Finally, we observed that CB-derived DNRII-transduced NK cells may protect surrounding immune cells by providing a cytokine sink for TGF-β (decreased TGF-β levels of 610 ± 265 pg/mL in CB-derived DNRII-transduced NK cells vs. 1817 ± 342 pg/mL in untransduced cells; p = 0.008). Conclusions CB NK cells expressing a TGF-β DNRII may have a functional advantage over unmodified NK cells in the presence of TGF-β-rich MB, warranting further investigation on its potential applications for patients with medulloblastoma.

scholarly journals Mechanism of Transforming Growth Factor β–induced Inhibition of T Helper Type 1 Differentiation

2002 ◽  
Vol 195 (11) ◽  
pp. 1499-1505 ◽  
Author(s):  
Leonid Gorelik ◽  
Stephanie Constant ◽  
Richard A. Flavell
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Inhibitory Effect ◽  
Interleukin 12 ◽  
T Helper ◽  
Retroviral Transduction ◽  
Cell Functions ◽  
Proliferation And Differentiation ◽  
Direct Inhibitory Effect

Regulation by transforming growth factor (TGF)-β plays an important role in immune homeostasis. TGF-β inhibits T cell functions by blocking both proliferation and differentiation. Here we show that TGF-β blocks Th1 differentiation by inhibiting the expression of T-bet, the apparent masterregulator of T helper (Th)1 differentiation. Restoration of T-bet expression through retroviral transduction of T-bet into developing Th1 cells abrogated the inhibitory effect of TGF-β. In addition, we show that, contrary to prior suggestions, downregulation of interleukin 12 receptor β2 chain is not key to the TGF-β–mediated effect. Furthermore, we show that the direct inhibitory effect of TGF-β on T cells is responsible, at least in part, for the inability of BALB/c mice to mount a Leishmania-specific Th1 response and to clear Leishmanial infection.

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