loxoribine and Inflammation

Human innate immunity plays a pivotal role in host defense against various microbial challenges. Mediated by a family of Toll-like-receptors (TLR) and associated intracellular downstream signaling molecules, human innate immunity can specifically recognize diverse microbial products and many other non-microbial environmental cues. Beyond its role of providing first line of defense, activation of innate immunity signaling can lead to expression of diverse pro- and anti- inflammatory mediators, which are critical for regulating various cell and tissue metabolism. Alteration in innate immunity signaling may therefore lead to infection and inflammatory diseases such as atherosclerosis, diabetes, and cancer. TLR receptors as well as intracellular signaling proteins can serve as therapeutic targets for treating various inflammatory diseases. Several synthetic ligands of TLR receptors such as lipid A analogs, poly(I:C), loxoribine, oligodeoxynucleotides have been shown to be effective in regulating innate immune response. This review discusses the potential, challenge, and recent progress of developing synthetic as well as naturally occurring TLR ligands in regulating innate immunity and treating inflammatory diseases.

Topics: Biological Products; Guanosine; Humans; Immunity, Innate; Inflammation; Ligands; Lipid A; Oligodeoxyribonucleotides; Poly I-C; Signal Transduction; Toll-Like Receptors

The induction of the autophagy machinery, a process for the catabolism of cytosolic proteins and organelles, constitutes a crucial mechanism in innate immunity. However, the involvement of autophagy in human neutrophils and the possible inducers of this process have not been completely elucidated. In this study, the induction of autophagy was examined in human neutrophils treated with various activators and detected by the formation of acidified autophagosomes through monodansylcadaverine staining and via LC-3B conversion screened by immunoblotting and immunofluorescence confocal microscopy. In addition, the expression of the ATG genes was assessed by real-time RT-PCR. We provide evidence that autophagy is implicated in human neutrophils in both a phagocytosis-independent (rapamycin, TLR agonists, PMA) and phagocytosis (Escherichia coli)-dependent initiation manner. ROS activation is a positive mechanism for autophagy induction in the case of PMA, TLR activation and phagocytosis. Furthermore, LC3B gene expression was uniformly upregulated, indicating a transcriptional level of regulation for the autophagic machinery. This study provides a stepping stone toward further investigation of autophagy in neutrophil-driven inflammatory disorders.

Topics: Adenine; Autophagy; Cadaverine; Chromones; Coloring Agents; Escherichia coli; Guanosine; Humans; Hydrogen-Ion Concentration; Inflammation; Microscopy, Confocal; Morpholines; Neutrophils; Phagosomes; Poly I-C; Reactive Oxygen Species; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; Sirolimus; Small Ubiquitin-Related Modifier Proteins; Tetradecanoylphorbol Acetate; Toll-Like Receptors; Transcription, Genetic; Vacuoles

Activation of astrocytes and microglia and the production of proinflammatory cytokines and chemokines are often associated with virus infection in the CNS as well as a number of neurological diseases of unknown etiology. These inflammatory responses may be initiated by recognition of pathogen-associated molecular patterns (PAMPs) that stimulate TLRs. TLR7 and TLR8 were identified as eliciting antiviral effects when stimulated by viral ssRNA. In the present study, we examined the potential of TLR7 and/or TLR8 agonists to induce glial activation and neuroinflammation in the CNS by intracerebroventricular inoculation of TLR7 and/or TLR8 agonists in newborn mice. The TLR7 agonist imiquimod induced astrocyte activation and up-regulation of proinflammatory cytokines and chemokines, including IFN-beta, TNF, CCL2, and CXCL10. However, these responses were only of short duration when compared with responses induced by the TLR4 agonist LPS. Interestingly, some of the TLR7 and/or TLR8 agonists differed in their ability to activate glial cells as evidenced by their ability to induce cytokine and chemokine expression both in vivo and in vitro. Thus, TLR7 stimulation can induce neuroinflammatory responses in the brain, but individual TLR7 agonists may differ in their ability to stimulate cells of the CNS.

Topics: Adjuvants, Immunologic; Aminoquinolines; Animals; Animals, Newborn; Astrocytes; Brain; Cell Line; Central Nervous System; Cytokines; Guanosine; Imidazoles; Imiquimod; Inflammation; Lipopolysaccharides; Mice; Mice, Inbred Strains; Mice, Mutant Strains; Quinolines; Toll-Like Receptor 7; Toll-Like Receptor 8

Topics: Cell Proliferation; Cell Survival; Guanosine; Humans; Inflammation; Ligands; Multiple Myeloma; Oligodeoxyribonucleotides; Toll-Like Receptors