Role of IL-6 and NF-kB signalling mediators in CD28-induced IL-17A gene expression and Th17 cell subset expansion

Proponente Loretta Tuosto - Professore Associato
Sottosettore ERC del proponente del progetto
Componenti gruppo di ricerca

The immunopathogenesis of several inflammatory and autoimmune diseases relies on both the amplification and persistence of pro-inflammatory Th17 cells. Therefore, the characterization of the mechanisms and molecules regulating the expansion of pro-inflammatory Th17 cells could represent an important goal of the ongoing research in inflammation and autoimmunity.
We have previously demonstrated that human CD28 costimulatory receptor, in the absence of TCR engagement, activates a NF-kB2-like pathway that leads to the up-regulation of pro-inflammatory cytokines related to the Th17 cell profile phenotype. More recently we showed that CD28-mediated up-regulation of IL-17A gene expression requires IL-6-induced signalling. Altogether these data strongly suggest a cooperation between IL-6-associated signalling mediators and NF-kB in CD28-mediated IL-17A expression and Th17 cell subset expansion. For instance, the 1-kb region upstream of the human IL-17A gene contains a putative binding site for NF-kB close to the binding site for STAT3, strongly supporting a potential cooperation between these two transcription factors in IL-17A transcription.
The present project will be aimed to characterize the role of IL-6-associated signalling mediators and NF-kB transcription factors in regulating CD28-induced IL-17A gene expression and Th17 cell subset expansion. To reach this goal we will proceed with the following tasks:
- Role of IL-6-associated STAT3 and RelA/NF-kB transcription transcription factors in regulating IL-17A promoter transactivation in CD28-stimulated T cells
- Functional relevance of IL-6 and NF-kB signalling pathways in regulating IL-17A gene expression and Th17 subset amplification in CD28-stimulated T cells
The major goal of this project is to provide biological bases for single or combined immunotherapeutic approaches targeting CD28-associated signalling mediators, such as IL-6/STAT3 and NF-kB, in order to dampen IL-17A-production in inflammatory diseases

LS6_2, LS1_10, LS2_5

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