Ureaplasma parvum lipoproteins, including MB antigen, activate NF-κB through TLR1, TLR2 and TLR6

Abstract

Ureaplasma species (Ureaplasma parvum and Ureaplasma urealyticum) are commonly isolated pathogens from the female reproductive tract and are associated with perinatal diseases in humans. Inappropriate induction of inflammatory responses may be involved in the occurrence of such diseases; however, pathogenic agents that induce the inflammatory response have not been identified in ureaplasmas. In this study, we examined the involvement of Toll-like receptors (TLRs) in the activation of the immune response by U. parvum lipoproteins, as well as the U. parvum components responsible for nuclear factor kB (NF-kB) activation. The Triton X-114 (TX-114) detergent phase of U. parvum was found to induce NF-kB through TLR2. The active components of the TX-114 detergent phase were lipoproteins, such as multiple banded (MB) antigen, UU012 and UU016 of U. parvum. The activation of NF-kB by these lipoproteins was inhibited by dominant negative (DN) constructs of TLR1 and DN TLR6. Thus, the lipoproteins from U. parvum were found to activate NF-kB through TLR1, TLR2 and TLR6. Furthermore, these lipoproteins possessed an ability to induce tumour necrosis factor-alpha (TNF-a) in mouse peritoneal macrophages. INTRODUCTIONUreaplasmas are wall-less bacteria belonging to the Mycoplasmataceae.Although Ureaplasma species (Ureaplasma parvum and Ureaplasma urealyticum) are common commensals of the urogenital tract of humans, ureaplasmas have frequently been recognized as important pathogens associated with non-gonococcal urethritis (Shepard, 1954), chorioamnionitis (Cassell et al., 1986;Maher et al., 1994), preterm birth (Jelsema, 2006;Kataoka et al., 2006; Ollikainen et al., 1998), infertility (TaylorRobinson, 1986;Xu et al., 1997), pneumonia in neonates (Waites et al., 1989) and bronchopulmonary dysplasia in neonates (Schelonka et al., 2005). The mechanisms by which ureaplasmas cause such diseases are unclear, but the inappropriate induction of inflammatory responses may be involved. It has been reported that the levels of interleukin-6 (IL-6), tumour necrosis factor-alpha (TNF-a), IL-1b and IL-8 in intra-amniotic fluid infected with ureaplasmas are increased (Yoon et al., 1998). Moreover, macrophages are capable of producing such cytokines and nitric oxide in response to U. urealyticum (Li et al., 2000a, b). However, pathogenic agents such as endotoxin and exotoxin that induce an inflammatory response have not been identified in ureaplasmas.It has been widely known that Toll-like receptors (TLRs) with the function of pattern-recognition receptors play critical roles in early innate recognition and inflammatory responses by the host against invading microbes (Akira & Takeda, 2004;Kopp & Medzhitov, 1999). Among 10 TLR family members reported, TLR2, TLR4, TLR5 and TLR9 have been implicated in the recognition of different bacterial components. Peptidoglycan (PGN), lipoarabinomannan, zymosan and lipoproteins from various microorganisms are recognized by TLR2 (Aliprantis et al., 1999;Brightbill et al., 1999;Lien et al., 1999;Means et al., 1999...

Interaction of Mycoplasma hominis PG21 with Human Dendritic Cells: Interleukin-23-Inducing Mycoplasmal Lipoproteins and Inflammasome Activation of the Cell

“…Many mycoplasmal lipoproteins have been reported to be involved in adhesion to host cells but also in the recognition by the host immune system (1). Indeed, mycoplasmal lipoproteins can act as proinflammatory factors and can stimulate human macrophages and human dendritic cells (hDCs), induce cytokine production, activate NF-B, and polarize the adaptive immune response (2)(3)(4)(5)(6)(7)(8). Nondenaturing detergent extracts, such as Triton X-114 (TX-114) extracts enriched with mycoplasmal lipoproteins, were shown to have modulatory capacities (2,5,6,9,10).…”

“…Indeed, mycoplasmal lipoproteins can act as proinflammatory factors and can stimulate human macrophages and human dendritic cells (hDCs), induce cytokine production, activate NF-B, and polarize the adaptive immune response (2)(3)(4)(5)(6)(7)(8). Nondenaturing detergent extracts, such as Triton X-114 (TX-114) extracts enriched with mycoplasmal lipoproteins, were shown to have modulatory capacities (2,5,6,9,10). In addition, synthetic lipopeptides derived from lipoproteins such as MALP-2 from Mycoplasma fermentans (11), FSL-1 from M. salivarium (12), and MPPL-1 from M. pneumoniae (13) were shown to have immunomodulatory properties.…”

Lung Diseases - Selected State of the Art Reviews

“…Additionally, free radical generation and oxidative injury induced by recruited neutrophils could contribute to lung damage [Buss et al, 2003]. Apoptosis of pneumocytes and pulmonary mesenchymal cells has been shown to occur as part of the pathogenesis of U. urealyticum , while U. parvum lipoproteins activate NF-kB and induce TNF- in macrophages, favoring the inflammatory response (Shimizu et al, 2008). Apparently, there is no trend in the prevalence of either species between infants with or without bronchopulmonary dysplasia .…”

Animal models of bronchopulmonary dysplasia. The preterm baboon models

“…Specifically, Ureaplasma lipoproteins promote activation of the NF-B pathway (68). TLR2 and TLR4 mRNA and protein expression are low in 125-day and 140-day gestation, nonventilated fetal baboon lung.…”