Lipoxin A4 (LXA4) is an endogenous lipid mediator with potent anti-inflammatory actions but its role in infectious processes is not well understood. We investigated the involvement of LXA4 and its receptor FPR2/ALX in the septic inflammatory dysregulation. Pneumosepsis was induced in mice by inoculation of Klebsiella pneumoniae. LXA4 levels and FPR2/ALX expression in the infectious focus as well as the effects of treatment with receptor agonists (LXA4 and BML-111) and antagonists (BOC-2 and WRW(4)) in early (1h) and late (24h) sepsis were studied. Sepsis induced an early increase in LXA4, FPR2/ALX lung expression, local and systemic infection and inflammation, and mortality. Treatment with BOC-2 in early sepsis increased leukocyte migration to the focus, and reduced bacterial load and dissemination. Inhibition of 5- and 15-lipoxygenase in early sepsis also increased leukocyte migration. Early treatment with WRW(4) and BOC-2 improved survival. Treatment with authentic LXA4 or BML-111 in early sepsis decreased cell migration and worsened the infection. In late sepsis, treatment with BOC-2 had no effect, but LXA4 improved the survival rate by reducing the excessive inflammatory response, this effect being abolished by pretreatment with BOC-2. Thus, the anti-inflammatory and pro-resolution mediator LXA4 and its receptor FPR2/ALX levels were increased in the early phase of sepsis, contributing to the septic inflammatory dysregulation. In addition, LXA4 has a dual role in sepsis and that its beneficial or harmful effects are critically dependent on the time. Therefore, a proper interference with LXA4 system may be a new therapeutic avenue to treat sepsis.

In the population studied, HPV-16 may not have participated in the pathogenesis of chronic periodontitis, and the gingival tissue did not act as a reservoir for this virus.

Proinflammatory cytokines are critical mediators that control Mycobacterium tuberculosis (Mtb) growth during active tuberculosis (ATB). To further inhibit bacterial proliferation in diseased individuals, drug inhibitors of cell wall synthesis such as isoniazid (INH) areemployed. However, whether INH presents an indirect effect on bacterial growth by regulating host cytokines during ATB is not well known. To examine this hypothesis, we used an in vitro human granuloma system generated with primary leukocytes from healthy donors adapted to model ATB. Intense Mtb proliferation in cell cultures was associated with monocyte/macrophage activation and secretion of IL-1β and TNF. Treatment with INH significantly reduced Mtb survival, but altered neither T-cell-mediated Mtb killing, nor production of IL-1β and TNF. However, blockade of both IL-1R1 and TNF signaling rescued INH-induced killing, suggesting synergistic roles of these cytokines in mediating control of Mtb proliferation. Additionally, mycobacterial killing by INH was highly dependent upon drug activation by the pathogen catalase-peroxidase KatG and involved a host PI3K-dependent pathway. Finally, experiments using coinfected (KatG-mutated and H37Rv strains) cells suggested that active INH does not directly enhance host-mediated killing of Mtb. Our results thus indicate that Mtb-stimulated host IL-1 and TNF have potential roles in TB chemotherapy.Keywords: Human r IL-1 r TNF r Isoniazid r Leukocytes r Mycobacterium tuberculosis Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionUpon Mycobacterium tuberculosis (Mtb) exposure, it is estimated that 5-10% of human subjects will develop active tuberculosis Correspondence: Prof. André Báfica e-mail: andre.bafica@ufsc.br (TB) [1], which is characterized by intense pathogen proliferation associated with cellular activation and cell death. Cellular structures known as necrotic granulomas may promote bacterial dissemination and enhance Mtb transmission [2,3]. On the other hand, counter balance is supported by host recognition of Mtb, which induces cytokines such as IL-1β and TNF [4,5], two potent inflammatory mediators that suppress Mtb growth [4,6]. It has C 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2016. 46: 1936-1947 Immunity to infection 1937 been shown that these cytokines regulate intracellular bacterial growth in human macrophages, whether by recruitment of antimicrobial effector molecules [7] or induction of apoptotic cell death [8]. In conjunction with 9], IL-1β, and TNF can provide signals to help differentiation and antigen presentation by macrophages [6,10,11]. Moreover, the adverse outcome of latent TB reactivation observed in clinical trials with anti-TNF therapies, additionally confirmed the essential role of TNF for controlling Mtb growth in humans [12]. In addition to antibiotics, which are major therapeutic tools to promote further suppression of mycobacterial growth [13], host-targeted i...

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