Progesterone minimizes immunoprotective effect of CpG ODN against infection by skewing immune responses toward Th17 (136.2)

Abstract Oligodeoxynucleotides encoding CpG motifs (CpG ODN), which activate the innate immune system and promote a strong Th1 response, are currently being tested in therapies for allergies and infectious diseases, including cutaneous leishmaniasis. Steroid hormones (such as progesterone) are associated with suppression of pro-inflammatory immune responses and a shift away from Th1 responses - critical for clearing intracellular parasites. Our assessment of progesterone effects on immune responses by mouse splenocytes in vitro and in vivo demonstrated a shift in the responses to CpG ODN characterized by limited upregulation of MHC Class II molecules by antigen presenting cells, lower IL-12 and IL-6, and increased IL-23 production. This was associated with increased IL-17 and lower IFN-γ secretion by CD4+ helper T cells. Similarly, progesterone treatment of human PBMCs stimulated with CpG ODN limited upregulation of CD83 and CD86 and decreased IFN-γ and IP-10 production. Assessment of whether the shift from Th1 responses by progesterone reduces the immunoprotective effects of CpG ODN in mice challenged with Leishmania major showed that orchiectomized mice receiving progesterone developed larger lesions than those receiving placebo and were not protected from disease when treated with CpG ODN. These data indicate that progesterone is able to skew immune responses by CpG ODN towards Th17 and contribute to disease susceptibility in women.