Pathway of NF-kB Activation

核 細胞質

Bacteria

Pathway of NF-kB ActivationCytokine such as TNF-, and environmental hazards such as inonizingradiation, toxic substances trigger the nuclear translocation of NK-kB via activation of inhibitor-of- NF-kB (IkB) kinase complex (IKK). IKK phosphorylates IkB bound to NF-kB which consists of a dimer of Relfamily proteins such as p65 and p50. This phosphorylation is the signal forubiquitination of IkB by a ubiquitin ligase (UbL). This produces IkB for degradation by the proteasomes, which then results in the release of NF-kB.The transcription factor is now free to become translocated to the nucleuswhere it binds to specific DNA elements and activates transcription of NF-kB-dependent genes.

Nitric Oxide (NO)

- a cell mediator regulates numerous physiological processes• neuro-transmission• smooth muscle contractility• platelet reactivity• cytotoxic activity of immune cellsinappropriate release of NO has been linked to the patho- genesis of a number of disease states !! Overproduction of NO by synthase: septic shock, neuro- degenerative disorders, and inflammationInhibitors of NO synthase

Nitrous oxide (N2O): agent for general anesthesia

Most of the physiological actions are brought by its activation of the soluble guanylate cyclase; increase about ~400 fold and formation of cGMP (second messenger)Prolonged exposure of NO inhibits the activity of a number of enzymes; aconitase, cytochrome c oxidase and DNA synthesis is impaired by the inhibitory action of NO on RNA

reductase; cytotoxic action of NO is produced on invading

micro-organisms.

Mechanism of Action of NO

NO Synthase

An enzyme has four isozymes• nNOS (or NOS I); regulated by Ca++ and calmodulin, and found in neural cells and human bronchi epithelium and skeletal muscle. • iNOS (or NOS II); Ca++ -independent form and induced by inflammatory mediator, and exist a variety of cells• eNOS (or NOS III); Ca++/calmodulin requiring, exists in vascular endothelial cells and a variety of neuronal cells including brain catalyze the enzymatic reaction with L-arginine (substrate) and requires various cofactors producing NO.

Fatty Acid

Arachidonicacid

Cox-1Cox-2

Prostaglandin

PG: Prostaglandin

Replication cycle of HIV

Replication cycle of HIVThe viral envelope protein (Env) of HIV binds CD4 first, undergoes a conformationalchange, then binds one of two chemokine receptors (CCR5 and CXCR4) and enters cells by fusion of the viral and cellular membranes. Uncoating of the viral capsid releases thepre-integration complex, which is routed to nuclear pores, along the microtubular networks.Reversetranscription yields double-stranded viral complementary DNA, which integratesinto host genome. Viral mRNA are transcribed from promoter elements in the 5’ LTR region.Cellular activation increases the level of transcription, which is augmented greatly by theviral transcriptional transactivator protein (Tat). Regulator of virion gene expressioin (Rev)transport singly spliced (ss) and unspliced genomic transcripts from the nucleus to cytoplasm.Viral structure and enzymatic proteins are synthesized and transported to the plasma membrane. Late domains in group-specific antigen (Gag) then recruit components of multi-vesicular bodies to the site of budding so that progeny virions are released from the infectedcells. The four accessory proteins (Nef, Vif, Vpr, and Vpu) and two regulatory proteins (Rev and Tat) are represented colored circles.Peterlin, B.M. and D. Trono, 2003. Hide, shield, and strike back; how HIV-infected cellsavoid immune eradication. Nat Rev Immunol. 3:97~107.