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Deprecated: Implicit conversion from float 211.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 J+Virol 2014 ; 88 (19): 11045-55 Nephropedia Template TP
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HIV-1 gp120 Activates the STAT3/Interleukin-6 Axis in Primary Human Monocyte-Derived Dendritic Cells #MMPMID25008924
Del Cornò M; Donninelli G; Varano B; Da Sacco L; Masotti A; Gessani S
J Virol 2014[Oct]; 88 (19): 11045-55 PMID25008924show ga
Dendritic cells (DCs) are fundamental for the initiation of immune responses and are important players in AIDS immunopathogenesis. The modulation of DC functional activities represents a strategic mechanism for HIV-1 to evade immune surveillance. Impairment of DC function may result from bystander effects of HIV-1 envelope proteins independently of direct HIV-1 infection. In this study, we report that exposure of immature monocyte-derived DCs (MDDCs) to HIV-1 R5 gp120 resulted in the CCR5-dependent production of interleukin-6 (IL-6) via mitogen-activated protein kinase (MAPK)/NF-?B pathways. IL-6 in turn activated STAT3 by an autocrine loop. Concomitantly, gp120 promoted an early activation of STAT3 that further contributed to IL-6 induction. This activation paralleled a concomitant upregulation of the STAT3 inhibitor PIAS3. Notably, STAT3/IL-6 pathway activation was not affected by the CCR5-specific ligand CCL4. These results identify STAT3 as a key signaling intermediate activated by gp120 in MDDCs and highlight the existence of a virus-induced dysregulation of the IL-6/STAT3 axis. HIV-1 gp120 signaling through STAT3 may provide an explanation for the impairment of DC function observed upon HIV exposure.IMPORTANCE This study provides new evidence for the molecular mechanisms and signaling pathways triggered by HIV-1 gp120 in human DCs in the absence of productive infection, emphasizing a role of aberrant signaling in early virus-host interaction, contributing to viral pathogenesis. We identified STAT3 as a key component in the gp120-mediated signaling cascade involving MAPK and NF-?B components and ultimately leading to IL-6 secretion. STAT3 now is recognized as a key regulator of DC functions. Thus, the identification of this transcription factor as a signaling molecule mediating some of gp120's biological effects unveils a new mechanism by which HIV-1 may deregulate DC functions and contribute to AIDS pathogenesis.
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J+Virol 2014 ; 88 (19): 11045-55
