Porth's Pathophysiology, 9e

Chapter 13 Innate and Adaptive Immunity    279

Chemokines are named according to structure, followed by “L” and the number of their gene ( e.g., CCL1, CXCL1). Likewise, chemokine receptors are named according to the structure, followed by an “R” and a number ( e.g., CCR1, CXCR1). Six receptors for CXC (CXCRs) and 10 for CC (CCRs) chemokines have been characterized in terms of their structure and function. 2 Chemokines communicate with their target cells by activating G-protein–coupled receptors that are pertussis toxin sensitive and as a result are capable of activat- ing different populations of leukocytes, thereby controlling the migration of immune cells to their sites of action based upon the needs of the situation. 2 Most receptors recognize more than one chemokine, and most chemokines recognize more than one receptor. Binding of a chemokine to a receptor can result in inhibition or activation with the same chemo- kine acting as an activator at one type of receptor and as an inhibitor at another. Chemokines are implicated in a num- ber of acute and chronic diseases, including atherosclerosis, rheumatoid arthritis, inflammatory bowel disease (Crohn disease, ulcerative colitis), allergic asthma and chronic bron- chitis, multiple sclerosis, systemic lupus erythematosus, and HIV infection. They also play a role in the body’s immune response against cancer cells through the up-regulation of CCL21 and other chemokines by activated T cells and other tumor-derived proteins. 7,8 Colony-Stimulating Factors Colony-stimulating factors (CSFs) encompass a subset of cytokines that participate in hematopoiesis by stimulating bone marrow pluripotent stem and progenitor or precursor cells to produce large numbers of mature platelets, erythro- cytes, lymphocytes, neutrophils, monocytes, eosinophils, basophils, and dendritic cells (DCs). The CSFs were named according to the type of target cell on which they act (see Table 13.2). Macrophages, endothelial cells, and fibroblasts produce granulocyte colony-stimulating factor (G-CSF) during times of stress and inflammation where it promotes growth and maturation of neutrophils. Granulocyte/monocyte colony-stimulating factor (GM-CSF) acts on the granulocyte– monocyte progenitor cells to produce monocytes, neutrophils, and DCs, and monocyte colony-stimulating factor (M-CSF) stimulates the mononuclear phagocyte progenitor. While CSF is necessary for normal blood cell production and maturation, excess CSF production has been implicated in several disease processes and the development of corticosteroid-resistant chronic obstructive pulmonary disease (COPD). 9 Impaired macrophage function and subsequent impairment of G-CSF activity have been associated with the development of neu- trophilia in animal studies. 10 In clinical practice, recombinant CSF is being used to increase the success rates of bone mar- row transplantations. The availability of recombinant CSFs and cytokines offers the possibility of several clinical thera- pies where stimulation or inhibition of the immune response or cell production is desirable.

formed molecules but rather are synthesized through tran- scription as a result of cellular activation. The actions of cytokines are often pleiotropic, meaning that they have the ability to allow a single cytokine to act on different cell types. For example, IL-17 is produced by the T-helper 17 (T 17 H) cells and acts on several cell types including leukocytes, epi- thelial cells, mesothelial cells, vascular endothelial cells, and fibroblasts. As a result, T 17 H cells play a critical role in host defense against pathogens that infiltrate the mucosal barrier. 5 Although pleiotropism allows cytokines to mediate diverse effects, it greatly limits their use for therapeutic purposes because of numerous unwanted side effects. Redundancy refers to the ability of different cytokines to stimulate the same or overlapping biologic functions. Because of this redundancy, antagonists against a single cytokine may not have functional consequences because other cytokines may compensate. In addition to being pleiotropic and redundant, cyto- kines can have broad activity. Therefore, several different cell types are capable of producing a single cytokine. For example, IL-1 is a proinflammatory cytokine that is primarily produced by macrophages but can be produced by virtually all leukocytes, endothelial cells, and fibroblasts. Cytokines also function to initiate cascade functions with one cytokine influencing the synthesis and actions of other cytokines. Often the second and third cytokines may mediate the bio- logic effects of the first cytokine. These effects may be local- ized, acting on a single cell or group of cells in the area sur- rounding the effector cell, or the effects can be systemic with the cytokines secreted into the bloodstream and transported to their site of action. TNF- α is an example of a cytokine with wide-­reaching systemic effects. Cytokines may also serve as antagonists to inhibit the action of another cytokine and as a result act as anti-inflammatory cytokines. IL-110 is an anti- inflammatory cytokine to down-regulate the inflammatory and adaptive immune responses. Chemokines Chemokines are small protein molecules (70 to 130 amino acids) that are involved in immune and inflammatory cellu- lar responses and function to control the migration of leuko- cytes to their primary site of action in the immune response. 6 There are four distinct classes of chemokines (C, CC, CXC, and CX3C), which are named for the number and location of cysteine residues on the terminal amino acid of the protein. 2 Currently, 48 distinct chemokine molecules have been iden- tified within the four different classes. The vast majority of these are classified as either CC or CXC chemokines. The CC chemokines have the first two cysteine molecules adjacent to each other, while these molecules are separated by an amino acid in the CXC chemokines. The CC chemokines attract monocytes, lymphocytes, and eosinophils to sites of chronic inflammation. The CXC chemokines attract neutrophils to sites of acute inflammation.