Abstract
This study aimed at investigating the effect of progesterone on interferon signaling pathways in peripheral blood mononuclear cells (PBMCs) of patients infected with hepatitis C virus (HCV). PBMCs were isolated from peripheral blood of 38 treatment-naïve HCV-infected patients, pooled, and stimulated with progesterone in the presence and absence of its receptor antagonist, mifepristone, along with interferon alpha (IFN-α) or imiquimod. Toll-like receptor (TLR) 7 and myxovirus resistance protein A (MxA) were quantified in PBMCs using RT-qPCR. Imiquimod alone or combined with progesterone did not change MxA expression in HCV-infected PBMCs. Progesterone decreased the inducing effect of IFN-α on TLR-7 expression in both males and females. Moreover, progesterone stimulation prior to IFN-α treatment attenuated the Jak/STAT pathway, which was reflected by decreased expression of MxA in females. Progesterone showed a negative impact on the IFN signaling pathway in HCV-infected PBMCs as it decreased the expression of TLR-7 in both genders, while MxA expression was decreased only in females.
Similar content being viewed by others
References
Akira S, Takeda K (2004) Toll-like receptor signalling. Nat Rev Immunol 4:499–511
Gilliet M, Cao W, Liu YJ (2008) Plasmacytoid dendritic cells: sensing nucleic acids in viral infection and autoimmune diseases. Nat Rev Immunol 8:594–606
Lund JM, Alexopoulou L, Sato A, Karow M, Adams NC, Gale NW, Iwasaki A, Flavell RA (2004) Recognition of single-stranded RNA viruses by toll-like receptor 7. Proc Natl Acad Sci USA 101:5598–5603
Smith PL, Lombardi G, Foster GR (2005) Type I interferons and the innate immune response-more than just antiviral cytokines. Mol Immunol 42:869–877
Williams BR (1991) Transcriptional regulation of interferon-stimulated genes. Eur J Biochem 200:1–11
Arnheiter H, Frese M, Kambadur R, Meier E, Haller O (1996) Mx transgenic mice-animal models of health. Curr Top Microbiol Immunol 206:119–147
Kittlesen DJ, Chianese-Bullock KA, Yao ZQ, Braciale TJ, Hahn YS (2000) Interaction between complement receptor gC1qR and hepatitis C virus core protein inhibits T-lymphocyte proliferation. J Clin Invest 106:1239–1249
Weber F, Kochs G, Haller O (2004) Inverse interference: how viruses fight the interferon system. Viral Immunol 17:498–515
Berghofer B, Frommer T, Haley G, Fink L, Bein G, Hackstein H (2006) TLR7 ligands induce higher IFN-alpha production in females. J Immunol 177:2088–2096
Escribese MM, Kraus T, Rhee E, Fernandez-Sesma A, Lopez CB, Moran TM (2008) Estrogen inhibits dendritic cell maturation to RNA viruses. Blood 112:4574–4584
Li X, Xu Y, Ma L, Sun L, Fu G, Hou Y (2009) 17beta-estradiol enhances the response of plasmacytoid dendritic cell to CpG. PLoS One 4:e8412
Fawzy IO, Negm M, Ahmed R, Esmat G, Hamdi N, Abdelaziz AI (2012) Tamoxifen alleviates hepatitis C virus-induced inhibition of both toll-like receptor 7 and JAK-STAT signalling pathways in PBMCs of infected Egyptian females. J Viral Hepat 19:854–861
Mekky RY, Hamdi N, El-Akel W, Esmat G, Abdelaziz AI (2010) Estrogen-related MxA transcriptional variation in hepatitis C virus-infected patients. Transl Res 159:190–196
Dosiou C, Hamilton AE, Pang Y, Overgaard MT, Tulac S, Dong J, Thomas P, Giudice LC (2008) Expression of membrane progesterone receptors on human T lymphocytes and Jurkat cells and activation of G-proteins by progesterone. J Endocrinol 196:67–77
Hughes GC, Thomas S, Li C, Kaja MK, Clark EA (2008) Cutting edge: progesterone regulates IFN-alpha production by plasmacytoid dendritic cells. J Immunol 180:2029–2033
Kalo-Klein A, Witkin SS (1989) Candida albicans: cellular immune system interactions during different stages of the menstrual cycle. Am J Obstet Gynecol 161:1132–1136
Nelson JL, Ostensen M (1997) Pregnancy and rheumatoid arthritis. Rheum Dis Clin North Am 23:195–212
Marks MA, Gravitt PE, Burk RD, Studentsov Y, Farzadegan H, Klein SL (2010) Progesterone and 17beta-estradiol enhance regulatory responses to human papillomavirus type 16 virus-like particles in peripheral blood mononuclear cells from healthy women. Clin Vaccine Immunol 17:609–617
Yuan Y, Shimizu I, Shen M, Aoyagi E, Takenaka H, Itagaki T, Urata M, Sannomiya K, Kohno N, Tamaki K, Shono M, Takayama T (2008) Effects of estradiol and progesterone on the proinflammatory cytokine production by mononuclear cells from patients with chronic hepatitis C. World J Gastroenterol 14:2200–2207
Poynard T, McHutchison J, Goodman Z, Ling MH, Albrecht J (2000) Is an “a la carte” combination interferon alfa-2b plus ribavirin regimen possible for the first line treatment in patients with chronic hepatitis C? The ALGOVIRC project group. Hepatology 31:211–218
Gilli F, Marnetto F, Caldano M, Sala A, Malucchi S, Capobianco M, Bertolotto A (2006) Biological markers of interferon-beta therapy: comparison among interferon-stimulated genes MxA, TRAIL and XAF-1. Mult Scler 12:47–57
Ito M, Masumi A, Mochida K, Kukihara H, Moriishi K, Matsuura Y, Yamaguchi K, Mizuochi T (2010) Peripheral B cells may serve as a reservoir for persistent hepatitis C virus infection. J Innate Immun 2:607–617
Colonna M, Krug A, Cella M (2002) Interferon-producing cells: on the front line in immune responses against pathogens. Curr Opin Immunol 14:373–379
Saleh MA, Mekky RY, El-Ekiaby N, Hamdi N, Ahmed R, Zekri AR, Esmat G, Abdelaziz AI (2012) Potent inhibitory effects of p7 inhibitors on genotype 4 HCV-infected peripheral blood mononuclear cells. Recent Pat Biomark 2:227–233
Thomas A, Laxton C, Joanne R, Myangar N, Horscroft N, Parkinson T (2007) Investigating toll-like receptor agonists for potential to treat hepatitis C virus infection. Antimicrob Agents Chemother 51:2969–2978
El-Ekiaby N, Hamdi N, Negm M, Ahmed R, Zekri AR, Esmat G, Abdelaziz AI (2012) Repressed induction of interferon-related microRNAs miR-146a and miR-155 in peripheral blood mononuclear cells infected with HCV genotype 4. FEBS Open Bio 2:179–186
Shaker O, Ahmed A, Doss W, Abdel-Hamid M (2010) MxA expression as marker for assessing the therapeutic response in HCV genotype 4 Egyptian patients. J Viral Hepat 17:794–799
Chang S, Kodys K, Szabo G (2010) Impaired expression and function of toll-like receptor 7 in hepatitis C virus infection in human hepatoma cells. Hepatology 51:35–42
Osterlund P, Veckman V, Siren J, Klucher KM, Hiscott J, Matikainen S, Julkunen I (2005) Gene expression and antiviral activity of alpha/beta interferons and interleukin-29 in virus-infected human myeloid dendritic cells. J Virol 79:9608–9617
Peluso JJ, Fernandez G, Pappalardo A, White BA (2001) Characterization of a putative membrane receptor for progesterone in rat granulosa cells. Biol Reprod 65:94–101
Taylor MW, Tsukahara T, Brodsky L, Schaley J, Sanda C, Stephens MJ, McClintick JN, Edenberg HJ, Li L, Tavis JE, Howell C, Belle SH (2007) Changes in gene expression during pegylated interferon and ribavirin therapy of chronic hepatitis C virus distinguish responders from nonresponders to antiviral therapy. J Virol 81:3391–3401
Hannah MF, Bajic VB, Klein SL (2008) Sex differences in the recognition of and innate antiviral responses to Seoul virus in Norway rats. Brain Behav Immun 22:503–516
Acknowledgment
This work was funded by the German University in Cairo postgraduate fund.
Conflict of interest
The authors declare that they have no conflict of interest.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Tayel, S.S., Helmy, A.A., Ahmed, R. et al. Progesterone suppresses interferon signaling by repressing TLR-7 and MxA expression in peripheral blood mononuclear cells of patients infected with hepatitis C virus. Arch Virol 158, 1755–1764 (2013). https://doi.org/10.1007/s00705-013-1673-z
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00705-013-1673-z