Objective To characterize the effect of HIV infection on IL-27-induced gene expression. Design During HIV infection, cytokine expression and function become deregulated. IL-27 is an important modulator of inflammatory responses. Interestingly, IL-27 can inhibit HIV replication in T cells and monocytes, implicating IL-27 as a potential adjunct to anti-viral treatment. Our previous work demonstrated that circulating HIV may suppress IL-27 expression, therefore, this study, in continuation of our previous work, aimed to understand how HIV affects expression levels of the IL-27 receptor and downstream functions of IL-27. Methods Peripheral blood mononuclear cells (PBMC) were isolated from whole blood of HIV negative and HIV positive (viremic) individuals to assess IL-27-induced gene expression by flow cytometry and ELISA. PBMC were also processed for monocyte enrichment to assess IL-27 receptor expression by flow cytometry and real-time PCR. Results Expression of the IL-27 receptor subunit, gp130, was upregulated in response to IL-27 in HIV negative individuals, however, in HIV positive individuals, this IL-27 response was diminished. Furthermore, we observed downregulation of IL-27-induced IL-6, TNF-α, and IL-10 expression in HIV positive subjects. Conclusion In HIV infection, IL-27-induced gene expression was impaired, indicating HIV-mediated dysregulation of IL-27 functions occurs during HIV infection. This study provides evidence for new viral pathogenic mechanisms contributing to the widespread impairment of immune responses observed in HIV pathogenesis.
References
[1]
Batten M, Ghilardi N (2007) The biology and therapeutic potential of interleukin 27. J Mol Med 85: 661–672.
[2]
Gee K, Guzzo C, Che Mat NF, Ma W, Kumar A (2009) The IL-12 family of cytokines in infection, inflammation and autoimmune disorders. Inflamm Allergy Drug Targets 8: 40–52.
[3]
Pflanz S, Hibbert L, Mattson J, Rosales R, Vaisberg E, et al. (2004) WSX-1 and glycoprotein 130 constitute a signal-transducing receptor for IL-27. J Immunol 172: 2225–2231.
Chen Q, Ghilardi N, Wang H, Baker T, Xie MH, et al. (2000) Development of Th1-type immune responses requires the type I cytokine receptor TCCR. Nature 407: 916–920.
[6]
Sprecher CA, Grant FJ, Baumgartner JW, Presnell SR, Schrader SK, et al. (1998) Cloning and characterization of a novel class I cytokine receptor. Biochem Biophys Res Commun 246: 82–90.
[7]
Wirtz S, Tubbe I, Galle PR, Schild HJ, Birkenbach M, et al. (2006) Protection from lethal septic peritonitis by neutralizing the biological function of interleukin 27. J Exp Med 203: 1875–1881.
[8]
Larousserie F, Charlot P, Bardel E, Froger J, Kastelein RA, et al. (2006) Differential effects of IL-27 on human B cell subsets. J Immunol 176: 5890–5897.
[9]
Lucas S, Ghilardi N, Li J, de Sauvage FJ (2003) IL-27 regulates IL-12 responsiveness of naive CD4+ T cells through Stat1-dependent and -independent mechanisms. Proc Natl Acad Sci U S A 100: 15047–15052.
[10]
Ruckerl D, Hessmann M, Yoshimoto T, Ehlers S, Holscher C (2006) Alternatively activated macrophages express the IL-27 receptor alpha chain WSX-1. Immunobiology 211: 427–436.
[11]
Guzzo C, Ayer A, Basta S, Banfield BW, Gee K (2012) IL-27 Enhances LPS-Induced Proinflammatory Cytokine Production via Upregulation of TLR4 Expression and Signaling in Human Monocytes. J Immunol 188: 864–873.
[12]
Guzzo C, Che Mat NF, Gee K (2010) Interleukin-27 induces a STAT1/3- and NF-kappaB-dependent proinflammatory cytokine profile in human monocytes. J Biol Chem 285: 24404–24411.
[13]
Greenwell-Wild T, Vazquez N, Jin W, Rangel Z, Munson PJ, et al. (2009) Interleukin-27 inhibition of HIV-1 involves an intermediate induction of type I interferon. Blood 114: 1864–1874.
[14]
Imamichi T, Yang J, Huang DW, Brann TW, Fullmer BA, et al. (2008) IL-27, a novel anti-HIV cytokine, activates multiple interferon-inducible genes in macrophages. AIDS 22: 39–45.
[15]
Guzzo C, Hopman WM, Mat NF, Wobeser W, Gee K (2010) Impact of HIV infection, highly active antiretroviral therapy, and hepatitis C coinfection on serum interleukin-27. AIDS 24: 1371–1374.
[16]
Schneider R, Yaneva T, Beauseigle D, El-Khoury L, Arbour N (2011) IL-27 increases the proliferation and effector functions of human naive CD8+ T lymphocytes and promotes their development into Tc1 cells. Eur J Immunol 41: 47–59.
[17]
Wong CK, Chen da P, Tam LS, Li EK, Yin YB, et al. (2010) Effects of inflammatory cytokine IL-27 on the activation of fibroblast-like synoviocytes in rheumatoid arthritis. Arthritis Res Ther 12: R129.
[18]
Murugaiyan G, Mittal A, Lopez-Diego R, Maier LM, Anderson DE, et al. (2009) IL-27 is a key regulator of IL-10 and IL-17 production by human CD4+ T cells. J Immunol 183: 2435–2443.
[19]
de Arquer GR, Pena R, Cabrera C, Coma G, Ruiz-Hernandez R, et al. (2007) Skewed expression and up-regulation of the IL-12 and IL-18 receptors in resting and activated CD4 T cells from HIV-1-infected patients. J Leukoc Biol 82: 72–78.
[20]
Jones ML, Young JM, Huang QR, Puls RL, Webber CA, et al. (2003) Interleukin 12-augmented T cell proliferation of peripheral blood mononuclear cells from HIV-seropositive individuals is associated with interleukin 12 receptor beta 2 upregulation. AIDS Res Hum Retroviruses 19: 283–292.
[21]
Tjernlund A, Fleener Z, Behbahani H, Connick E, Sonnerborg A, et al. (2003) Suppression of leukemia inhibitor factor in lymphoid tissue in primary HIV infection: absence of HIV replication in gp130-positive cells. AIDS 17: 1303–1310.
[22]
McQuaid A, Tormey VJ, Trafford B, Webster AD, Bofill M (2003) Evidence for increased expression of regulatory cytokine receptors interleukin-12R and interleukin-18R in common variable immunodeficiency. Clin Exp Immunol 134: 321–327.
[23]
Alhetheel A, Yakubtsov Y, Abdkader K, Sant N, Diaz-Mitoma F, et al. (2008) Amplification of the signal transducer and activator of transcription I signaling pathway and its association with apoptosis in monocytes from HIV-infected patients. AIDS 22: 1137–1144.
[24]
Baqui AA, Jabra-Rizk MA, Kelley JI, Zhang M, Falkler WA Jr, et al. (2000) Enhanced interleukin-1beta, interleukin-6 and tumor necrosis factor-alpha production by LPS stimulated human monocytes isolated from HIV+ patients. Immunopharmacol Immunotoxicol 22: 401–421.
[25]
Birx DL, Redfield RR, Tencer K, Fowler A, Burke DS, et al. (1990) Induction of interleukin-6 during human immunodeficiency virus infection. Blood 76: 2303–2310.
[26]
Sadeghi HM, Weiss L, Kazatchkine MD, Haeffner-Cavaillon N (1995) Antiretroviral therapy suppresses the constitutive production of interleukin-1 associated with human immunodeficiency virus infection. J Infect Dis 172: 547–550.
[27]
Canque B, Rosenzwajg M, Gey A, Tartour E, Fridman WH, et al. (1996) Macrophage inflammatory protein-1alpha is induced by human immunodeficiency virus infection of monocyte-derived macrophages. Blood 87: 2011–2019.
[28]
Feng XM, Liu N, Yang SG, Hu LY, Chen XL, et al.. (2008) Regulation of the class II and class I MHC pathways in human THP-1 monocytic cells by interleukin-27. BiochemBiophysResCommun.
[29]
Tilton JC, Johnson AJ, Luskin MR, Manion MM, Yang J, et al. (2006) Diminished production of monocyte proinflammatory cytokines during human immunodeficiency virus viremia is mediated by type I interferons. J Virol 80: 11486–11497.
[30]
von Sydow M, Sonnerborg A, Gaines H, Strannegard O (1991) Interferon-alpha and tumor necrosis factor-alpha in serum of patients in various stages of HIV-1 infection. AIDS Res Hum Retroviruses 7: 375–380.
