Defective regulation of the proinflammatory immune response in women with vulvar vestibulitis syndrome


      Objective: The cause of vulvar vestibulitis syndrome is unknown. To determine a possible role for defective immune regulation in this chronic condition, proinflammatory and anti-inflammatory immune responses to the 70-kd heat shock protein and to lipopolysaccharide were compared in women with and without vulvar vestibulitis syndrome. Study design: Whole blood cultures from 62 women with vulvar vestibulitis syndrome and 48 control subjects were incubated in the presence or absence of 5 μg/mL human recombinant 70-kd heat shock protein or 0.1 ng/mL lipopolysaccharide for 18 hours. The culture supernatants were then assayed for interleukin-1β and interleukin-1 receptor antagonist by enzyme-linked immunosorbent assay. Results: Median levels of interleukin-1β were higher in response to heat shock protein in cultures from patients with vulvar vestibulitis syndrome (median, 1.07 ng/mL) as opposed to control subjects (median, 0.40 ng/mL; P = .006). Conversely, levels of interleukin-1 receptor antagonist were higher in response to heat shock protein in control subjects (median, 39.21 ng/mL) than in patients (median, 29.25 ng/mL; P = .009).In response to lipopolysaccharide, median levels of interleukin-1β were similar in patients (1.00 ng/mL) and control subjects (1.15 ng/mL); median interleukin-1 receptor antagonist concentrations were higher in control subjects (70.0 ng/mL) than in patients (44.3 ng/mL; P < .0001). The ratio of interleukin-1 receptor antagonist to interleukin-1β was higher in control subjects than in women with vulvar vestibulitis syndrome in response to both heat shock protein (P = .0002) and lipopolysaccharide (P = .01). In uninduced cultures, interleukin-1 receptor antagonist levels were also higher in control subjects (median, 1.60 ng/mL) than in patients with vulvar vestibulitis syndrome (median, 0.62 ng/mL; P < .0001). Conclusion: A relative inability to down-regulate proinflammatory interleukin-1β activity by interleukin-1 receptor antagonist may contribute to the pathophysiologic features of vulvar vestibulitis syndrome. (Am J Obstet Gynecol 2002;186:696-700.)


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to American Journal of Obstetrics & Gynecology
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Ledger WJ
        • Kessler A
        • Leonard GH
        • Witkin SS
        Vulvar vestibulitis: a complex clinical entity.
        Infect Dis Obstet Gynecol. 1996; 4: 269-275
        • Sarma AV
        • Foxman B
        • Bayirli B
        • Haefner H
        • Sobel JD
        Epidemiology of vulvar vestibulitis syndrome: an exploratory case-control study.
        Sex Transm Inf. 1999; 75: 320-326
        • Rogstad KE
        Vulvar vestibulitis: aetiology, diagnosis and treatment.
        Int J STD AIDS. 2000; 11: 557-562
        • Chadha S
        • Gianotten WL
        • Drogendijk AC
        • Weijmar Schultz WC
        • Blinderman LA
        • van der Meijden WI
        Histopathologic features of vulvar vestibulitis.
        Int J Gynecol Pathol. 1998; 17: 7-11
        • Foster DC
        • Hasday JD
        Elevated tissue levels of interleukin-1 beta and tumor necrosis factor-alpha in vulvar vestibulitis.
        Obstet Gynecol. 1997; 89: 291-296
        • Nyirjesy P
        • Halpern M
        Medical management of vulvar vestibulitis: results of a sequential treatment plan.
        Infect Dis Obstet Gynecol. 1996; 3: 193-197
        • Jeremias J
        • Ledger WJ
        • Witkin SS
        Interleukin 1 receptor antagonist gene polymorphism in women with vulvar vestibulitis.
        Am J Obstet Gynecol. 2000; 182: 283-285
        • Asea A
        • Kraeft SK
        • Kurt-Jones EA
        • Stevenson MA
        • Chen LB
        • Finberg RW
        • et al.
        HSP70 stimulates cytokine production through a CD14-dependent pathway, demonstrating its dual role as a chaperone and cytokine.
        Nature Med. 2000; 6: 435-442
        • McIntyre KW
        • Stepan GJ
        • Kolinsky KD
        • Benjamin WR
        • Plocinski JM
        • Kaffka KL
        • et al.
        Inhibition of interleukin 1 binding and bioactivity in vitro and modulation of acute inflammation in vivo by IL-1 receptor antagonist and anti-IL-1 receptor monoclonal antibody.
        J Exp Med. 1991; 173: 931-939
        • Granowitz EV
        • Santos AA
        • Poutsiaka DD
        • Cannon JG
        • Wilmore DW
        • Wolff SM
        • et al.
        Production of interleukin-1 receptor antagonist during experimental endotoxaemia.
        Lancet. 1991; 338: 1423-1424
        • Nerad JL
        • Griffiths JK
        • van der Meer JW
        • Endres S
        • Poutsiaka DD
        • Keusch GT
        • et al.
        Interleukin-1β, IL-1 receptor antagonist, and TNFα production in whole blood.
        J Leukoc Biol. 1992; 52: 687-692
        • Khosla S
        • Peterson JM
        • Egan K
        • Jones JD
        • Riggs BL
        Circulating cytokine levels in osteoporotic and normal women.
        J Clin Endocrinol Metab. 1994; 79: 707-711
        • DeGroote D
        • Zangerle PF
        • Gevaert Y
        • Fassotte MF
        • Beguin Y
        • Noizat-Pirenne F
        • et al.
        Direct stimulation of cytokines (IL-1β, TNF-α, IL-6, IL-2, IFN-γ_and GM-CSF) in whole blood, I: comparison with isolated PBMC stimulation.
        Cytokine. 1992; 4: 239-248
        • Casini-Raggi V
        • Kam L
        • Chong YJ
        • Fiocchi C
        • Pizarro TT
        • Cominelli F
        Mucosal imbalance of IL-1 and IL-1 receptor antagonist in inflammatory bowel disease: a novel mechanism of chronic intestinal inflammation.
        J Immunol. 1995; 154: 2434-2440
        • Young RA
        Stress proteins and immunology.
        Annu Rev Immunol. 1990; 8: 401-420
        • Horowitz BJ
        Interferon therapy for condylomatous vulvitis.
        Obstet Gynecol. 1989; 73: 446-448
        • Reznikov LL
        • Puren AJ
        • Fantuzzi G
        • Muhl H
        • Shapiro L
        • Yoon DY
        • et al.
        Spontaneous and inducible cytokine responses in healthy humans receiving a single dose of IFN-α2β: increased production of interleukin-1 receptor antagonist and suppression of IL-1-induced IL-8.
        J Interferon Cytokine Res. 1998; 18: 897-907
        • Dinarello CA
        Biologic basis for interleukin-1 in disease.
        Blood. 1996; 87: 2095-2147