Transforming growth factor-␤-activated kinase 1 (TAK1) plays an essential role in the tumor necrosis factor ␣ (TNF␣)-and interleukin-1␤ (IL-1␤)-induced IB kinase (IKK)/nuclear factor-B (NF-B) and c-Jun N-terminal kinase (JNK)/Tumor necrosis factor ␣ (TNF␣) 3 and interleukin-1␤ (IL-1␤) are two potent proinflammatory cytokines that play important roles in the regulation of immunity, inflammation, cell proliferation, differentiation, and apoptosis (1, 2). Cellular responses to TNF␣ and IL-1␤ are mediated by intracellular signaling pathways that control the activation of nuclear factor-B (NF-B) and activator protein 1 (AP-1) (3, 4).Upon binding to its receptor, TNF␣ induces formation of a receptor-associated complex, including the adaptor proteins TRADD, TRAF2, TRAF5, and RIP1, which subsequently leads to Lys 63 -linked polyubiquitination of TRAF2 and RIP1 (5-7). In contrast, IL-1␤ binding to its receptor induces a receptor-associated complex formation, including MyD88, IRAK1, IRAK4, and TRAF6, which is followed by Lys 63 -linked polyubiquitination of TRAF6 and IRAKs (8 -12). The formation of TRAF2-RIP1 and TRAF6-IRAK4 complexes as well as the Lys 63 -linked polyubiquitination of RIP1 and TRAF6 appear to enable the recruitment and activation of transforming growth factor-␤-activated kinase 1 (TAK1) through binding of the TAK1 regulatory subunits TAB2 and TAB3 to the Lys 63 -polyubiquitinated RIP1 and TRAF6. The activated TAK1 then triggers the activation of the IB kinase (IKK), c-Jun N-terminal kinase (JNK), and p38 MAPK (8,(13)(14)(15)(16)(17), which leads to activation of transcription factors NF-B and AP-1 and up-regulation of many genes encoding proinflammatory cytokines, chemokines, adhesion molecules, and proteolytic enzymes (18).The IKK complex consists of three subunits: two catalytic subunits, IKK␣ and IKK␤, and an essential regulatory subunit, IKK␥/NF-B essential modulator (NEMO) (3,19). Genetic studies have implicated that IKK␤ and IKK␥/NEMO are essential for the TNF␣-and IL-1␤-mediated . Phosphorylation of serine 177 and 181 residues in the activation loop is required for IKK␤ activation (23). IKK␥/NEMO has been indicated to bind Lys 63 -linked polyubiquitin chains (7,16,24,25). It is proposed that Lys 63 -polyubiquitin chains act as a scaffold to allow for assembly of a signaling complex that leads to IKK␤ activation. Once activated, IKK␤ phosphorylates IB proteins and leads to IB polyubiquitination with a Lys 48 -linked ubiquitin chain. Polyubiquitination-mediated degradation of IBs allows NF-B to translocate into the nucleus and activate NF-B-dependent gene expression (26).JNKs are members of three related mitogen-activated protein kinases (MAPKs), including the extracellular signal-regulated kinases (ERKs), JNKs, and p38 MAPKs (4, 27). JNKs and p38 MAPKs are involved in transmitting intracellular signals in

Therapeutic study, level IV.

Anemia and hemorrhagic shock are leading causes of morbidity and mortality worldwide, and transfusion of human blood products is the ideal treatment for these conditions. As human erythrocytes age during storage in blood banks they undergo many biochemical and structural changes, termed the red blood cell ‘storage lesion’. Specifically, ATP and pH levels decrease as metabolic end products, oxidative stress, cytokines, and cell-free hemoglobin increase. Also, membrane proteins and lipids undergo conformational and organizational changes that result in membrane loss, viscoelastic changes and microparticle formation. As a result, transfusion of aged blood is associated with a host of adverse consequences such as decreased tissue perfusion, increased risk of infection, and increased mortality. This review summarizes current research detailing the known parts of the erythrocyte storage lesion and their physiologic consequences.