Reduced IL-1β Production Research Articles

Flagellar Motility Is a Key Determinant of the Magnitude of the Inflammasome Response to Pseudomonas aeruginosa

We previously demonstrated that bacterial flagellar motility is a fundamental mechanism by which host phagocytes bind and ingest bacteria. Correspondingly, loss of bacterial motility, consistently observed in clinical isolates from chronic Pseudomonas aeruginosa infections, enables bacteria to evade association and ingestion of P. aeruginosa by phagocytes both in vitro and in vivo. Since bacterial interactions with the phagocyte cell surface are required for type three secretion system-dependent NLRC4 inflammasome activation by P. aeruginosa, we hypothesized that reduced bacterial association with phagocytes due to loss of bacterial motility, independent of flagellar expression, will lead to reduced inflammasome activation. Here we report that inflammasome activation is reduced in response to nonmotile P. aeruginosa. Nonmotile P. aeruginosa elicits reduced IL-1β production as well as caspase-1 activation by peritoneal macrophages and bone marrow-derived dendritic cells in vitro. Importantly, nonmotile P. aeruginosa also elicits reduced IL-1β levels in vivo in comparison to those elicited by wild-type P. aeruginosa. This is the first demonstration that loss of bacterial motility results in reduced inflammasome activation and antibacterial IL-1β host response. These results provide a critical insight into how the innate immune system responds to bacterial motility and, correspondingly, how pathogens have evolved mechanisms to evade the innate immune system.

Activation of the PI3K pathway increases TLR-induced TNF-α and IL-6 but reduces IL-1β production in mast cells

Recognition of bacterial constituents by mast cells (MCs) is dependent on the presence of pattern recognition receptors, such as Toll-like receptors (TLRs). The final cellular response, however, depends on the influence of multiple environmental factors. In the current study we tested the hypothesis that the PI3K-activating ligands insulin-like growth factor-1 (IGF-1), insulin, antigen, and Steel Factor (SF) are able to modulate the TLR4-mediated production of proinflammatory cytokines in murine MCs. Costimulation with any of these ligands caused increased LPS-triggered secretion of IL-6 and TNF-α, but attenuated the production of IL-1β, though all three cytokines were produced in an NFκB-dependent manner. The pan-specific PI3K-inhibitor Wortmannin reverted the altered production of these cytokines. In agreement, MCs deficient for SHIP1, a negative regulator of the PI3K pathway, showed augmented secretion of IL-6/TNF-α and reduced production of IL-1β in response to LPS alone. The differential effects of IGF-1 on TLR4-mediated cytokine production were also observed in the context of TLR2 and IL-33 receptor-mediated MC activation. Importantly, these effects were seen in both bone marrow-derived and peritoneal MCs, suggesting general relevance for MCs. Using pharmacological and genetic tools, we could show that the p110δ isoform of PI3K is strongly implicated in SF-triggered suppression of LPS-induced IL-1β production. Costimulation with antigen was affected to a lesser extent. In conclusion, NFκB-dependent production of proinflammatory cytokines in MCs is differentially controlled by PI3K-activating ligand/receptor systems.

Macrophage phagocytosis and lysozyme-based digestion of peptidoglycan are required for IL-1β production in response to S. aureus (134.38)

Abstract IL-1β produced by phagocytes is important for protection against Staphylococcus aureus, a bacterium that causes serious skin and invasive diseases and is contributing to a current public health crisis due to the emergence of methicillin-resistant strains. Secretion of IL-1β requires both activation of a transcriptional signal to stimulate production of pro- IL-1β, (usually provided by TLR signaling) and a second signal to stimulate processing by inflammasome complexes and release of the mature cytokine. We show here that phagocytosis and lysozyme-based degradation of bacterial cell walls are functionally coupled to activation of Nalp3 inflammasomes and secretion of IL-1β in response to live S. aureus and to S. aureus peptidoglycan. Further, a S. aureus peptidoglycan-modifying enzyme that makes its peptidoglycan resistant to lysozyme strongly suppresses inflammasome activation. This is the first demonstration of a case whereby a bacterium avoids IL-1β secretion through chemical modification of its cell wall peptidoglycan, and we hypothesize that this reduced IL-1β production is key to successful mucosal colonization and infection. This research is supported by grants from NIGMS and the American Heart Association.

Constituents of Oxandra cf. xylopioides with Anti-inflammatory Activity

A new triterpenoid (1) derived from 24-methylcycloartanol was isolated from the leaves of Oxandra cf. xylopioides. An unusual structure of the new compound was assigned as 1, for which the name berenjenol is proposed, on the basis of the spectroscopic data of the natural product and of its derivatives 2 and 3. The leaves also afforded the known monoterpene isoespintanol (4). Compounds 1 and 4 significantly reduced the paw edema induced by carrageenan by 64% and 43%, at 3 h, respectively. Moreover, 4 reduced IL-1 beta production by 72% at 100 microM and reduced IL-1 beta mRNA synthesis.

Caspase activation may be associated with Mycobacterium avium pathogenicity

Background M ycobacterium avium causes disseminated infection in immunocompromised patients and triggers a process resembling Crohn's disease in goats. Colony morphotypes predict pathogenicity. Smooth-transparent (SmT) morphotypes are more virulent and induce less interleukin (IL)-1β and IL-18 production than avirulent smooth-domed (SmD) morphotypes. Caspases are essential for IL-1β and IL-18 production. Methods Caspase activation was examined in human monocytes after M. avium infection. Results Fresh monocytes constitutively expressed caspase-1 mRNA and pro-caspase-1. The M. avium infection increased monocyte caspase-1 mRNA expression. Furthermore, SmD-infected monocytes expressed 2.3-fold higher levels ( P <0.05, n = 3) of activated caspases than SmT-infected monocytes. Caspase-1 inhibition significantly reduced IL-1β production by SmT- and SmD-infected monocytes ( P <0.05, n = 4). Caspase-3 inhibition inhibited IL-1β production 43.5% ± 8.0% ( P <0.02, n = 4) by SmD-infected but not SmT-infected monocytes. Conclusions Decreased mature IL-1β release by SmT-infected monocytes may reflect selective induction of caspase-1 activity but not caspase-3. Differential caspase expression in monocytes after infection may contribute to M. avium pathogenicity in humans.

Reduced IL-1β production is associated with altered T helper 1(Th1)/Th2 cytokine profile at the mRNA level in the decidua in unexplained recurrent pregnancy loss (RPL).

Objective: A maternal response to the conceptus known as Th1 immunodystrophism has been associated with unexplained RPL. However, a causal relationship and the underlying mechanism(s) remain to be determined. Our previous studies showed an association of IL-1β gene polymorphisms with Th1 immunity to trophoblast in RPL, suggesting that IL-1 is potentially involved in the etiology of this disorder. The objective of the current study was to correlate IL-1β and Th1/Th2 cytokine gene expression in the decidua from women with and without RPL corrected for fetal aneuploidy.