The ability of HIV-1 to exploit the host immune responses to its own advantage is critical in the pathogenesis of AIDS. Since dendritic cells (DCs) are key players in the induction of immune responses, the modulation of their functional activities represents a strategic mechanism for HIV-1 to evade immune surveillance. In this study, we report that exposure of immature monocyte-derived DCs (MDDCs) to recombinant gp120 transcriptionally activates IL-6 expression and promotes its secretion in a concentration and time-dependent manner. Activation of MAPK p38 is involved in gp120 triggered IL-6 over-expression as p38 specific inhibitors markedly reduced IL-6 secretion. IL-6 over-expression induces at later time points accumulation of the tyrosine phosphorylated form of STAT3. Blocking IL-6 biological activity resulted in a dramatic reduction of STAT3 activation suggesting that gp120 might interfere with the STAT3/IL-6 axis. Consistently with this hypothesis, blocking STAT3 activation markedly decreases IL-6 secretion. Reconstruction of the signaling pathway triggered by gp120 in MDDCs unraveled a biphasic activation of STAT3, triggered early on by gp120 and leading to IL-6 secretion which, at later time points, induces a second round of STAT3 activation. Moreover, the possible involvement of cellular microRNAs in the regulation of this process will be discussed. Overall, these results indicate that DCs may contribute to the up-modulation of IL-6 found in HIV infected individuals. Furthermore, chronic activation of STAT3 in DCs may provide an explanation for the impairment of DC functions

Immunomodulatory effects of Hiv-1 gp120 on human dendritic cells: role of stat3/il-6 axis / M., Del Cornò; Donninelli, Gloria; B., Varano; A., Masotti; L., Da Sacco; S., Gessani. - In: FRONTIERS IN IMMUNOLOGY. - ISSN 1664-3224. - (2013). (Intervento presentato al convegno ICI 2013 – 15th International Congress of Immunology tenutosi a Milano nel 22-27/08/2013) [doi: 10.3389/conf.fimmu.2013.02.00928].

Immunomodulatory effects of Hiv-1 gp120 on human dendritic cells: role of stat3/il-6 axis

DONNINELLI, GLORIA;
2013

Abstract

The ability of HIV-1 to exploit the host immune responses to its own advantage is critical in the pathogenesis of AIDS. Since dendritic cells (DCs) are key players in the induction of immune responses, the modulation of their functional activities represents a strategic mechanism for HIV-1 to evade immune surveillance. In this study, we report that exposure of immature monocyte-derived DCs (MDDCs) to recombinant gp120 transcriptionally activates IL-6 expression and promotes its secretion in a concentration and time-dependent manner. Activation of MAPK p38 is involved in gp120 triggered IL-6 over-expression as p38 specific inhibitors markedly reduced IL-6 secretion. IL-6 over-expression induces at later time points accumulation of the tyrosine phosphorylated form of STAT3. Blocking IL-6 biological activity resulted in a dramatic reduction of STAT3 activation suggesting that gp120 might interfere with the STAT3/IL-6 axis. Consistently with this hypothesis, blocking STAT3 activation markedly decreases IL-6 secretion. Reconstruction of the signaling pathway triggered by gp120 in MDDCs unraveled a biphasic activation of STAT3, triggered early on by gp120 and leading to IL-6 secretion which, at later time points, induces a second round of STAT3 activation. Moreover, the possible involvement of cellular microRNAs in the regulation of this process will be discussed. Overall, these results indicate that DCs may contribute to the up-modulation of IL-6 found in HIV infected individuals. Furthermore, chronic activation of STAT3 in DCs may provide an explanation for the impairment of DC functions
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/729663
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