Toll-Like Receptor Responsiveness of Peripheral Blood Mononuclear Cells in Young Women with Dysmenorrhea

Abstract

Susan F Evans,1 Yuen H Kwok,2 Ann Solterbeck,3 Jiajun Liu,2 Mark R Hutchinson,1,4 M Louise Hull,5 Paul E Rolan6 1Adelaide Medical School, University of Adelaide, Adelaide, South Australia, Australia; 2Faculty of Health Science, University of Adelaide, Adelaide, South Australia, Australia; 3Statistical Revelations, Melbourne, Victoria, Australia; 4Australian Research Council Centre of Excellence for Nanoscale BioPhotonics, University of Adelaide, Adelaide, South Australia, Australia; 5Robinson Research Institute, School or Pediatrics and Reproductive Health, University of Adelaide, Adelaide, South Australia, Australia; 6School of Medicine, University of Adelaide, Adelaide, South Australia, AustraliaCorrespondence: Susan F Evans Tel [phone]Email [email protected]: Dysmenorrhea is a common disorder that substantially disrupts the lives of young women. To determine whether there is evidence of activation of the innate immune system in dysmenorrhea and whether the degree of activation may be used as a biomarker for pain, we compared the responsiveness of peripheral blood mononuclear cells (PBMCs) to toll-like receptor (TLR) 2 or 4 stimulation. We also investigated whether this effect is modulated by the use of the oral contraceptive pill (OC).Patients and Methods: Fifty-six women aged 16– 35 years, with either severe or minimal dysmenorrhea, and use or non-use of the OC, were enrolled. PBMCs were collected on two occasions in a single menstrual cycle: the menstrual phase and the mid-follicular phase. PBMCs were exposed to lipopolysaccharide (LPS), a TLR4 agonist, and PAM3CSK4 (PAM), a TLR2 agonist, and the resulting interleukin-1beta (IL– 1β) output was determined. Statistical analysis compared the EC50 between groups as a measure of TLR responsiveness of PBMCs.Results: The key finding following LPS stimulation was a pain effect of dysmenorrhea (p=0.042) that was independent of use or non-use of OC, and independent of day of testing. Women with dysmenorrhea showed a large 2.15-fold (95% CI − 4.69, − 0.09) increase in IL– 1β release when compared with pain-free participants across both days.Conclusion: This is the first study to demonstrate an ex vivo immune relationship in women with dysmenorrhea-related pelvic pain. It provides evidence for the potential of immune modulation as a novel pharmacological target for future drug development in the management of dysmenorrhea.Keywords: pain, chronic pain, oral contraceptive pill, endometriosis, pelvic pain, IL-1β

Keywords

• pain
• chronic pain
• oral contraceptive pill
• endometriosis
• pelvic pain
• il-1β