Great lectures, thank you for making available! Regarding the importance of p38 mapk in maintaining tumor cell dormancy: The role of p38 mapk in organ-specific tissues such as epithelial cells, in cancer associated fibroblast or in stem-like cancer cells could be significantly different from the role of p38 mapk in activated T-cells, where it is necessary for the IL-12-induced IFN-gamma production due to the essential role of the p38 mapk/NFKB pathway in controling the full activation of the IL-12p35 subunit and, thus, high level IL-12p70. Upon DC-T-cell crosstalk, IL12RB2 activates p38 mapk upon the IL-2-induced STAT5-activated upregulation of IL12RB2 mRNA and protein expression. This early upregulation of IL12RB2 mRNA, before its well studied role in the differentiation from naive to TH1 effector T-cells during each cell division in the IL-12p70/STAT4/IFN-gamma axis, also initiates the JMJD3-mediated demethylation of H3K27me3 on PRC2-bound genes, as well as mediates Brg1 in the SWI/SNF complex, which provides chromatin opening and elongation in cooperation with the T-bet mediated H3K4me3 mark,- thereby representing a possible interface for cellular and molecular mechanisms during T-cell activation which includes the importance of p38 mapk in the functional synergy between CD25 and IL12RB2 during T-cell activation, proliferation, differentiation and even CD8+ cross-presentation due to a feedback signal to the DC via CD40L/CD40 interaction and its time-dependent termination. Interstingly, the co-expression of p38 mapk and IL12RB2 in i.a. lung cancer diagnosis as well as the loss of these 2 previously expressed genes in tumor progression and immune therapy resistence, suggests an important role for these 2 genes in immune control of tumors. IL12RB2 has been shown to activate p38 mapk, and IL12RB2 deletion has been shown to inhibit p38 mapk just as efficiently as the pharmacological inhibition of p38 mapk through p38-specific antagonists. This underlines the importance of studying immune cell/cancer stem-like cell crosstalk when evaluating p38 mapk inhibition in tumor patients. Furthermore, the regulatory role of IL12RB2 in cell fate choices involves the control of the fine-tuned termination of the enhancer located at the IL-6R which is necessary for the avoidance of IL-23-mediated TH17 inflammation due to the recently shown role of prolonged IL-6 receptor expression being necessary for the induction of patholigical IL-23 augmented TH17 inflammation. The above, can probably be studied in the mice model of IL12RB2 deletion, where the IL12RB2 knock-out mouse develops immunodefeciency, spontaneous autoimmunity, SLE-like vascular inflammation and cancers,- or in human cell lines with deletion of IL12RB2 on exon 1-3 including the intronic regions, where JMJD3 binds to three locations on the introns of IL12B2, initiating a stepwise process of post-translational histone modifications and transcriptional control.
Great lectures, thank you for making available!
Regarding the importance of p38 mapk in maintaining tumor cell dormancy:
The role of p38 mapk in organ-specific tissues such as epithelial cells, in cancer associated fibroblast or in stem-like cancer cells could be significantly different from the role of p38 mapk in activated T-cells, where it is necessary for the IL-12-induced IFN-gamma production due to the essential role of the p38 mapk/NFKB pathway in controling the full activation of the IL-12p35 subunit and, thus, high level IL-12p70.
Upon DC-T-cell crosstalk, IL12RB2 activates p38 mapk upon the IL-2-induced STAT5-activated upregulation of IL12RB2 mRNA and protein expression. This early upregulation of IL12RB2 mRNA, before its well studied role in the differentiation from naive to TH1 effector T-cells during each cell division in the IL-12p70/STAT4/IFN-gamma axis, also initiates the JMJD3-mediated demethylation of H3K27me3 on PRC2-bound genes, as well as mediates Brg1 in the SWI/SNF complex, which provides chromatin opening and elongation in cooperation with the T-bet mediated H3K4me3 mark,- thereby representing a possible interface for cellular and molecular mechanisms during T-cell activation which includes the importance of p38 mapk in the functional synergy between CD25 and IL12RB2 during T-cell activation, proliferation, differentiation and even CD8+ cross-presentation due to a feedback signal to the DC via CD40L/CD40 interaction and its time-dependent termination.
Interstingly, the co-expression of p38 mapk and IL12RB2 in i.a. lung cancer diagnosis as well as the loss of these 2 previously expressed genes in tumor progression and immune therapy resistence, suggests an important role for these 2 genes in immune control of tumors.
IL12RB2 has been shown to activate p38 mapk, and IL12RB2 deletion has been shown to inhibit p38 mapk just as efficiently as the pharmacological inhibition of p38 mapk through p38-specific antagonists. This underlines the importance of studying immune cell/cancer stem-like cell crosstalk when evaluating p38 mapk inhibition in tumor patients.
Furthermore, the regulatory role of IL12RB2 in cell fate choices involves the control of the fine-tuned termination of the enhancer located at the IL-6R which is necessary for the avoidance of IL-23-mediated TH17 inflammation due to the recently shown role of prolonged IL-6 receptor expression being necessary for the induction of patholigical IL-23 augmented TH17 inflammation.
The above, can probably be studied in the mice model of IL12RB2 deletion, where the IL12RB2 knock-out mouse develops immunodefeciency, spontaneous autoimmunity, SLE-like vascular inflammation and cancers,- or in human cell lines with deletion of IL12RB2 on exon 1-3 including the intronic regions, where JMJD3 binds to three locations on the introns of IL12B2, initiating a stepwise process of post-translational histone modifications and transcriptional control.
Great lecture. Thank you very much. Especially about senolytics it was quite exciting.
Thank you so much for this lecture!
Wow
Economy contributed to faster aging and forgetfulness