Inflammation

Caspases are a family of cysteine-aspartic acid proteases that cleave caspase proenzymes as well as other protein substrates. Caspases are well known for their role in apoptosis, but they also play a significant role in other cellular processes including inflammation (1). Apoptotic caspases include Caspases-3, -6, -7, -8, and -9. Meanwhile, human inflammatory caspases include Caspases-1, -4, -5, and -12.

Thrombomodulin, also known as BDCA-3, is a glycosylated transmembrane protein present on the surface of vascular endothelial cells. Thrombomodulin is a high-affinity receptor for thrombin, a key protein in the coagulation cascade. Formation of the thrombomodulin-thrombin complex blocks the thrombin dependent conversion of fibrinogen to fibrin and also catalyzes the activation of protein C. Active protein C is able to proteolytically inactivate enhancers of the coagulation cascade.

Matrix metalloproteinases (MMPs) are responsible for the degradation of extracellular matrix proteins. MMPs are essential for tissue remodeling during normal processes such as embryonic development as well as pathological conditions such as arthritis and tumor metastasis. MMP3, a member of the stromelysin family, has broad specificity for proteins such as collagens, fibronectin, proteoglycans, and elastin making it an important player in extracellular matrix remodeling. These activities are especially important during tumorigenesis by enhancing epithelial to mesenchymal transition.

Scavenger receptors play important roles in homeostasis and innate immunity by binding to endogenous and foreign molecules. Scavenger receptors on the plasma membrane of macrophages bind to ligand and allow their internalization and can also mediate pro- or anti-inflammatory signaling. The plasma membrane glycoprotein CD163 is a member of the scavenger receptor cysteine-rich (SRCR) protein family. CD163 contains nine SRCR domains and is expressed in macrophages and monocytes where it plays a role in innate immunity and regulation of inflammation in response to ligand binding.

The mammalian target of rapamycin (mTOR) signaling pathway allows cells to monitor environmental signals like nutrient availability and oxygen levels. mTOR is a phosphoinositide 3-kinase (PI3K)-related protein that assembles into large protein complexes (mTORC1 and mTORC2) capable of regulating cell metabolism, growth, and proliferation.

The inhibitor of apoptosis proteins (IAPs) are important regulators of cell death and inflammation. The cellular inhibitor of apoptosis protein 2 (cIAP2) contains three Baculovirus IAP repeat (BIR) domains, a Ubiquitin associated (UBA) domain, and a RING domain with E3 ligase activity. cIAP2 inhibits apoptosis through direct inhibition of the pro-apoptotic caspase-3. cIAP2 also regulates cell survival through its role in the tumor necrosis factor alpha (TNF-alpha) signaling pathway.

IL-1 was originally identified and cloned as a lymphocyte mitogen and much later, was found to be comprised of two closely related but distinct proteins, interleukin 1 alpha (IL-1 alpha) and interleukin 1 beta (IL-1 beta). Both these proteins bind to the same cell surface receptor. IL-1 is primarily released from stimulated macrophages, but is also released from several other cell types. Along with other IL-1 gene family members, IL-1 beta falls within a cytokine gene cluster on chromosome 2.

The complement system is made up of a collection of proteins found in the bloodstream and is comprised of nine major complement proteins; complement C3 is one of them. The complement system is a crucial component of the cellular immune system because it kills unwanted bacteria and initiates inflammation. Within the complement system family of proteins, C3 is the most plentiful as well as most central protein, and consists of an alpha and a beta chain. The C3 activation step represents the convergence of the lectin, classical, and alternative complement activation pathways.

Chemokines play a central role in inflammation and are crucial for recruitment of immune cells to sites of infection. The chemokine-dependent activation of leukocytes occurs through binding to G-protein coupled receptors. These chemokine receptor subtypes can be divided into two major groups, CXCR and CCR.

The protein P2Y2 is a G-protein coupled metabotropic receptor that belongs to a larger family consisting of several receptor subtypes that each has a different pharmacological selectivity for various adenosine and uridine nucleotides. (This selectivity overlaps in some cases).