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Gene set enrichment analysis identifies LIF as a negative regulator of human Th2 cell differentiation.

Ullah U, Tripathi P, Lahesmaa R, Rao KV - Sci Rep (2012)

Bottom Line: In this study we show that IL-4 is crucial during reinforcement window of human Th2 differentiation for optimal Th2 development.We have also shown here that during this stage, IL-4 helps in cellular decision-making process of differentiation versus proliferation.This approach can be generalized to analyze "omics" data to identify key regulatory modules.

View Article: PubMed Central - PubMed

Affiliation: Immunology Group International Centre for Genetic Engineering and Biotechnology, Aruna Asaf Ali Marg, New Delhi-110067, India.

ABSTRACT
In this study we show that IL-4 is crucial during reinforcement window of human Th2 differentiation for optimal Th2 development. We have also shown here that during this stage, IL-4 helps in cellular decision-making process of differentiation versus proliferation. We have combined computational and experimental methods to analyze Th2 transcription network to name novel players of the process of Th2 differentiation. Here we report that LIF through STAT3 negatively regulates Th2 differentiation. This approach can be generalized to analyze "omics" data to identify key regulatory modules.

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Related in: MedlinePlus

STAT3 Phosphorylation in response to different stimuli.Panel a shows pSTAT3 profile obtained in a flow experiment. Unstimulated, TCR triggered and TCR + IL4 treated samples are show in Red, Blue or Green color respectively. In panel b Red is TCR + IL-4 treated, Blue is TCR + LIF treated, green is TCR + anti-LIF treated. In panel c TCR + IL-4 is Red TCR + IL-4 + anti-IFNG is Blue and TCR + LIF + anti-IFNG is green. Results represent experiment done at least in duplicate.
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f5: STAT3 Phosphorylation in response to different stimuli.Panel a shows pSTAT3 profile obtained in a flow experiment. Unstimulated, TCR triggered and TCR + IL4 treated samples are show in Red, Blue or Green color respectively. In panel b Red is TCR + IL-4 treated, Blue is TCR + LIF treated, green is TCR + anti-LIF treated. In panel c TCR + IL-4 is Red TCR + IL-4 + anti-IFNG is Blue and TCR + LIF + anti-IFNG is green. Results represent experiment done at least in duplicate.

Mentions: A recent study reported the role of STAT3 in Th2 differentiation and there it was observed that STAT3 phosphorylation peaks at day 3 followed by a steady decline. We, therefore, studied STAT3 phosphorylation by LIF and IL-4 at day 3 post stimulation. Figure 5a shows pSTAT3 profile either in unstimulated cells (Red) or after TCR triggering in presence (Green) or absence (Blue) of IL-4. We observed that both TCR and TCR + IL-4 show similar profile with TCR + IL-4 having slightly more phosphorylation than TCR alone. TCR + LIF treated cells, on the other hand, had much less phosphorylation, as compared to TCR or TCR + IL-4 treated cells suggesting that LIF may inhibit sustained STAT3 phosphorylation (Figure 5b). We also observed pSTAT3 level in the presence of anti-IFNγ and found that the profile for TCR + IL-4 in the presence (Blue) or absence (Red) of anti-IFNγ were similar (Figure 5c). Thus, taken together results in Figure 5 suggest that although LIF is secreted by Th2 cells it inhibits the differentiation of naïve cells into Th2 by reducing sustained phosphorylation of STAT3.


Gene set enrichment analysis identifies LIF as a negative regulator of human Th2 cell differentiation.

Ullah U, Tripathi P, Lahesmaa R, Rao KV - Sci Rep (2012)

STAT3 Phosphorylation in response to different stimuli.Panel a shows pSTAT3 profile obtained in a flow experiment. Unstimulated, TCR triggered and TCR + IL4 treated samples are show in Red, Blue or Green color respectively. In panel b Red is TCR + IL-4 treated, Blue is TCR + LIF treated, green is TCR + anti-LIF treated. In panel c TCR + IL-4 is Red TCR + IL-4 + anti-IFNG is Blue and TCR + LIF + anti-IFNG is green. Results represent experiment done at least in duplicate.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3376453&req=5

f5: STAT3 Phosphorylation in response to different stimuli.Panel a shows pSTAT3 profile obtained in a flow experiment. Unstimulated, TCR triggered and TCR + IL4 treated samples are show in Red, Blue or Green color respectively. In panel b Red is TCR + IL-4 treated, Blue is TCR + LIF treated, green is TCR + anti-LIF treated. In panel c TCR + IL-4 is Red TCR + IL-4 + anti-IFNG is Blue and TCR + LIF + anti-IFNG is green. Results represent experiment done at least in duplicate.
Mentions: A recent study reported the role of STAT3 in Th2 differentiation and there it was observed that STAT3 phosphorylation peaks at day 3 followed by a steady decline. We, therefore, studied STAT3 phosphorylation by LIF and IL-4 at day 3 post stimulation. Figure 5a shows pSTAT3 profile either in unstimulated cells (Red) or after TCR triggering in presence (Green) or absence (Blue) of IL-4. We observed that both TCR and TCR + IL-4 show similar profile with TCR + IL-4 having slightly more phosphorylation than TCR alone. TCR + LIF treated cells, on the other hand, had much less phosphorylation, as compared to TCR or TCR + IL-4 treated cells suggesting that LIF may inhibit sustained STAT3 phosphorylation (Figure 5b). We also observed pSTAT3 level in the presence of anti-IFNγ and found that the profile for TCR + IL-4 in the presence (Blue) or absence (Red) of anti-IFNγ were similar (Figure 5c). Thus, taken together results in Figure 5 suggest that although LIF is secreted by Th2 cells it inhibits the differentiation of naïve cells into Th2 by reducing sustained phosphorylation of STAT3.

Bottom Line: In this study we show that IL-4 is crucial during reinforcement window of human Th2 differentiation for optimal Th2 development.We have also shown here that during this stage, IL-4 helps in cellular decision-making process of differentiation versus proliferation.This approach can be generalized to analyze "omics" data to identify key regulatory modules.

View Article: PubMed Central - PubMed

Affiliation: Immunology Group International Centre for Genetic Engineering and Biotechnology, Aruna Asaf Ali Marg, New Delhi-110067, India.

ABSTRACT
In this study we show that IL-4 is crucial during reinforcement window of human Th2 differentiation for optimal Th2 development. We have also shown here that during this stage, IL-4 helps in cellular decision-making process of differentiation versus proliferation. We have combined computational and experimental methods to analyze Th2 transcription network to name novel players of the process of Th2 differentiation. Here we report that LIF through STAT3 negatively regulates Th2 differentiation. This approach can be generalized to analyze "omics" data to identify key regulatory modules.

Show MeSH
Related in: MedlinePlus