HIV-1 gp120 Activates the STAT3/Interleukin-6 Axis in Primary Human Monocyte-Derived Dendritic Cells

Cornò, Manuela Del; Donninelli, Gloria; Varano, Barbara; Sacco, Letizia Da; Masotti, Andrea; Gessani, Sandra

doi:10.1128/jvi.00307-14

Cited by 51 publications

(52 citation statements)

References 62 publications

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“…To elucidate the signaling pathways, we focused on STAT3 as it plays critical role in IL-6 production in cancer and infectious diseases2627 and STAT3 and its regulator suppressor of cytokine signaling (SOCS)3 are critical in TB2829. To this end, we evaluated phosphorylation of STAT3 in macrophages stimulated with ESAT-6.…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Early Secreted Antigenic Target of 6-kDa of Mycobacterium tuberculosis Stimulates IL-6 Production by Macrophages through Activation of STAT3

Jung

Wang

et al. 2017

Sci Rep

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As early secreted antigenic target of 6 kDa (ESAT-6) of Mycobacterium tuberculosis (Mtb) is an essential virulence factor and macrophages are critical for tuberculosis infection and immunity, we studied ESAT-6 stimulated IL-6 production by macrophages. ESAT-6 stimulated significantly higher IL-6 secretion by murine bone marrow derived macrophages (BMDM) compared to culture filtrate protein 10 kDa (CFP10) and antigen 85A. Polymyxin B, an LPS blocker, did not affect ESAT-6 stimulated macrophage IL-6 production. ESAT-6 but not Pam3CSK4 induced IL-6 by TLR2 knockout BMDM. ESAT-6 induced phosphorylation and DNA binding of STAT3 and this was blocked by STAT3 inhibitors but not by rapamycin. STAT3 inhibitors suppressed ESAT-6-induced IL-6 transcription and secretion without affecting cell viability. This was confirmed by silencing STAT3 in macrophages. Blocking neither IL-6Rα/IL-6 nor IL-10 affected ESAT-6-induced STAT3 activation and IL-6 production. Infection of BMDM and human macrophages with Mtb with esat-6 deletion induced diminished STAT3 activation and reduced IL-6 production compared to wild type and esat-6 complemented Mtb strains. Administration of ESAT-6 but not CFP10 induced STAT3 phosphorylation and IL-6 expression in the mouse lungs, consistent with expression of ESAT-6, IL-6 and phosphorylated-STAT3 in Mtb-infected mouse lungs. We conclude that ESAT-6 stimulates macrophage IL-6 production through STAT3 activation.

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Section: Resultsmentioning

confidence: 99%

“…This mechanism is also shared by several other pathogens606162 including HIV63. HSP60 of Helicobacter pylori 64 and gp120 of HIV have been shown to stimulate IL-627. Therefore, activation of STAT3 and induction of IL-6 production may be a common mechanism shared by a variety of pathogenic microorganisms including Mtb .…”

Section: Discussionmentioning

confidence: 99%

Early Secreted Antigenic Target of 6-kDa of Mycobacterium tuberculosis Stimulates IL-6 Production by Macrophages through Activation of STAT3

Jung

Wang

et al. 2017

Sci Rep

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“…The HIV gp120 IIIB protein could thus disrupt the CAP by indirectly interfering with JAK2 recruitment to the α7, JAK2 autophosphorylation, the phosphorylation of STAT3 or the nuclear translocation of dimerized STAT3, among other possibilities. In fact, a recent work proposed that gp120 signaling through STAT3 may explain the impairment of dendritic cells upon HIV exposure 54 …”

Section: Discussionmentioning

confidence: 99%

The α7‐nicotinic receptor is upregulated in immune cells from HIV‐seropositive women: consequences to the cholinergic anti‐inflammatory response

et al. 2015

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Antiretroviral therapy partially restores the immune system and markedly increases life expectancy of HIV-infected patients. However, antiretroviral therapy does not restore full health. These patients suffer from poorly understood chronic inflammation that causes a number of AIDS and non-AIDS complications. Here we show that chronic inflammation in HIV+ patients may be due to the disruption of the cholinergic anti-inflammatory pathway by HIV envelope protein gp120IIIB. Our results demonstrate that HIV gp120IIIB induces α7 nicotinic acetylcholine receptor (α7) upregulation and a paradoxical proinflammatory phenotype in macrophages, as activation of the upregulated α7 is no longer capable of inhibiting the release of proinflammatory cytokines. Our results demonstrate that disruption of the cholinergic-mediated anti-inflammatory response can result from an HIV protein. Collectively, these findings suggest that HIV tampering with a natural strategy to control inflammation could contribute to a crucial, unresolved problem of HIV infection: chronic inflammation.

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“…IL-6 is a major cytokine in the CNS that is secreted by various brain cells and has a number of physiological functions (Erta et al 2012), including behavior regulation (Erta et al 2015). Moreover, IL-6 expression was previously reported to be induced by HIV-1 Tat, gpl20, and Nef (Del Como et al 2014; Liu and Kumar 2015; Nookala and Kumar 2014). Its level in the CNS is also increased by EtOH exposure (Doremus-Fitzwater et al 2015; Gano et al 2016).…”

Section: Discussionmentioning

confidence: 99%

Effects of docosahexaenoic acid on locomotor activity in ethanol-treated HIV-1 transgenic rats

Huang

Zheng

et al. 2017

J. Neurovirol.

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Binge drinking affects the onset and progression of human immunodeficiency virus (HIV)-associated neurological disorders. The HIV-1 transgenic (HIV-1Tg) rat was created with a gag- and pol-deleted HIV-1 viral genome to mimic HIV-infected patients receiving combination anti-retroviral therapy (cART). Docosahexaenoic acid (DHA) is a marine compound that modulates inflammatory responses. Using HIV-1Tg rats subjected to binge exposure to ethanol (EtOH), this study examined whether DHA could reduce the detrimental neurological effects of EtOH and HIV proteins. Young adult male HIV-1Tg and F344 control rats received 4 mL/kg/day saline as a control (Saline group), 20 mg/kg/day DHA (DHA group), 4.8 g/kg/day 52% w/v EtOH (EtOH group), or 4.8 g/kg/day 52% w/v EtOH and 20 mg/kg/d DHA (DHA + EtOH group) by gavage for 5 weeks (n = 6 per group). EtOH was administrated on days 5, 6, and 7 of each week. Locomotor activity (LMA) was assessed using open field tests before and 45, 90, 135, and 180 min after each treatment. Repeated binge EtOH exposure gradually decreased LMA measured before daily treatments in HIV-1Tg and F344 rats, an effect that was reversed by DHA only in the HIV-1Tg rats. Decreased LMA of rats after treatment and under the influence of EtOH was less pronounced, and the reversal effect of DHA did not reach statistical significance. The plasma endotoxin level was significantly higher in HIV-1Tg rats than in F344 rats. IL-6 and IL-18 expression in the striatum was significantly higher in the HIV-1Tg EtOH group than in the F344 EtOH group. DHA significantly decreased the high levels of IL-6, IL-18, and NF-κB expression observed in the HIV-1Tg EtOH group. DHA appears to ameliorate inflammation and consequently lessen the reductions in LMA produced by the combination of EtOH and HIV-1 viral proteins.

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HIV-1 gp120 Activates the STAT3/Interleukin-6 Axis in Primary Human Monocyte-Derived Dendritic Cells

Cited by 51 publications

References 62 publications

Early Secreted Antigenic Target of 6-kDa of Mycobacterium tuberculosis Stimulates IL-6 Production by Macrophages through Activation of STAT3

Early Secreted Antigenic Target of 6-kDa of Mycobacterium tuberculosis Stimulates IL-6 Production by Macrophages through Activation of STAT3

The α7‐nicotinic receptor is upregulated in immune cells from HIV‐seropositive women: consequences to the cholinergic anti‐inflammatory response

Effects of docosahexaenoic acid on locomotor activity in ethanol-treated HIV-1 transgenic rats

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