Abstract
Background: Ureaplasma species have been associated with chorioamnionitis and preterm birth and have been implicated in the pathogenesis of neonatal short and long-term morbidity. However, being mostly commensal bacteria, controversy remains on the pro-inflammatory capacity of Ureaplasma. Discussions are ongoing on the incidence and impact of prenatal, perinatal, and postnatal infection. The present study addressed the impact of Ureaplasma isolates on monocyte-driven inflammation.Methods: Cord blood monocytes of term neonates and adult monocytes, either native or LPS-primed, were cultured with Ureaplasma urealyticum (U. urealyticum) serovar 8 (Uu8) and Ureaplasma parvum serovar 3 (Up3). Using qRT-PCR, cytokine flow cytometry, and multi-analyte immunoassay, we assessed mRNA and protein expression of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-8, IL-12p40, IL-10, and IL-1 receptor antagonist (IL-1ra) as well as Toll-like receptor (TLR) 2 and TLR4.Results: Uu8 and Up3 induced mRNA expression and protein release of TNF-α, IL-1β and IL-8 in term neonatal and adult monocytes (p < 0.01 and p < 0.05). Intracellular protein expression of TNF-α, IL-1β and IL-8 in Ureaplasma-stimulated cells paralleled those results. Ureaplasma-induced cytokine levels did not significantly differ from LPS-mediated levels except for lower intracellular IL-1β in adult monocytes (Uu8: p < 0.05). Remarkably, ureaplasmas did not induce IL-12p40 response and promoted lower amounts of anti-inflammatory IL-10 and IL-1ra than LPS, provoking a cytokine imbalance more in favor of pro-inflammation (IL-1β/IL-10, IL-8/IL-10 and IL-8/IL-1ra: p < 0.01, vs. LPS). In contrast to LPS, both isolates induced TLR2 mRNA in neonatal and adult cells (p < 0.001 and p < 0.05) and suppressed TLR4 mRNA in adult monocytes (p < 0.05). Upon co-stimulation, Uu8 and Up3 inhibited LPS-induced intracellular IL-1β (p < 0.001 and p < 0.05) and IL-8 in adult monocytes (p < 0.01), while LPS-induced neonatal cytokines were maintained or aggravated (p < 0.05).Conclusion: Our data demonstrate a considerable pro-inflammatory capacity of Ureaplasma isolates in human monocytes. Stimulating pro-inflammatory cytokine responses while hardly inducing immunomodulatory and anti-inflammatory cytokines, ureaplasmas might push monocyte immune responses toward pro-inflammation. Inhibition of LPS-induced cytokines in adult monocytes in contrast to sustained inflammation in term neonatal monocytes indicates a differential modulation of host immune responses to a second stimulus. Modification of TLR2 and TLR4 expression may shape host susceptibility to inflammation.
Highlights
Ureaplasma urealyticum (U. urealyticum) and the separate species Ureaplasma parvum are generally regarded as commensal bacteria being detected in the lower genital tract of 40–80% of women of reproductive age (Abele-Horn et al, 1997; Volgmann et al, 2005; Hunjak et al, 2014)
Two Ureaplasma strains were used, both obtained from the American Tissue Culture Collection (ATCC) (European distributor LGC Standards GmbH, Wesel, Germany): ATCC U. urealyticum strain of serovar 8 (Uu8) (ATCC 27618) and ATCC U. parvum strain of serovar 3 (Up3) (ATCC 27815), both often associated with disease manifestation (Waites et al, 2009; Xiao et al, 2011)
Since pathogen-induced immune responses may be regulated at the level of transcription and translation, we correlated mRNA expression with protein secretion using Quantitative Real-Time Reverse Transcription Polymerase Chain Reaction (qRT-PCR) and multi-analyte immunoassay
Summary
Ureaplasma urealyticum (U. urealyticum) (serovars 2, 4, 5, 7–13) and the separate species Ureaplasma parvum (serovars 1, 3, 6, 14) are generally regarded as commensal bacteria being detected in the lower genital tract of 40–80% of women of reproductive age (Abele-Horn et al, 1997; Volgmann et al, 2005; Hunjak et al, 2014). Upper genital tract infection with Ureaplasma species (spp.) has been associated with chorioamnionitis (CA), adverse pregnancy outcome and preterm birth (i.e., delivery
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