• TNF regulates energy balance by promoting lipid and protein catabolism and by suppressing appetite. Therefore, sustained production of TNF contributes to cachexia, a pathologic state characterized by weight loss, muscle atrophy, and anorexia that accompanies some chronic infections and cancers.
As mentioned earlier, TNF antagonists have been remarkably effective in the treatment of chronic inflammatory diseases, particularly rheumatoid arthritis, psoriasis, and some types of inflammatory bowel disease. One complication of this therapy is increased susceptibility to mycobacterial infection, resulting from reduced ability of macrophages to kill intracellular microbes. Although many of the actions of TNF and IL-1 are overlapping, IL-1 antagonists are not as effective, for reasons that remain obscure. Also, blocking either cytokine has no effect on the outcome of sepsis, perhaps because other cytokines contribute to this serious systemic inflammatory reaction.
Chemokines are a family of small (8–10 kD) proteins that act primarily as chemoattractants for specific types of leukocytes. About 40 different chemokines and 20 different receptors for chemokines have been identified. They are classified into four major groups, according to the arrangement of cysteine (C) residues in the proteins:
C-X-C chemokines have one amino acid residue separating the first two of the four conserved cysteines. These chemokines act primarily on neutrophils. IL-8 (now called CXCL8) is typical of this group. It is secreted by activated macrophages, endothelial cells, and other cell types, and causes activation and chemotaxis of neutrophils, with limited activity on monocytes and eosinophils. Its most important inducers are microbial products and cytokines, mainly IL-1 and TNF.
C-C chemokines have the first two conserved cysteine residues adjacent. The C-C chemokines, which include monocyte chemoattractant protein (MCP-1, CCL2), eotaxin (CCL11), and macrophage inflammatory protein1α (MIP-1α, CCL3), mainly serve as chemoattractants for monocytes, eosinophils, basophils, and lymphocytes. Although most of the chemokines in this class have overlapping actions, eotaxin selectively recruits eosinophils.
C chemokines lack the first and third of the four conserved cysteines. The C chemokines (e.g., lymphotactin, XCL1) are relatively specific for lymphocytes.
CX3C chemokines contain three amino acids between the first two cysteines. The only known member of this class is called fractalkine (CX3CL1). This chemokine exists in two forms: a cell surface-bound protein induced on endothelial cells by inflammatory cytokines that promotes strong adhesion of monocytes and T cells, and a soluble form, derived by proteolysis of the membrane-bound protein, that has potent chemoattractant activity for the same cells.
Chemokines mediate their activities by binding to seven-transmembrane G protein–coupled receptors. These http://ebooksmedicine.net
Mediators of Inflammation 75
TNF,
Increased expression of adhesion molecules
IL-1, Leukocytes chemokines
IL-1, IL-6, receptors usually exhibit overlapping ligand specificities, and leukocytes generally express multiple receptors. As discussed in Chapter 5, certain chemokine receptors (CXCR4, CCR5) act as coreceptors for a viral envelope glycoprotein of human immunodeficiency virus (HIV), the cause of AIDS, and are thus involved in binding and entry of the virus into cells.
Chemokines bind to proteoglycans and are displayed at high concentrations on the surface of endothelial cells and in the extracellular matrix. They have two main functions: