Cytokines are hormone-like molecules that act—generally in a paracrine fashion—to regulate immune responses. They are secreted not only by lymphocytes and macrophages but by endothelial cells, neurons, glial cells, and other types of cells. Most of the cytokines were initially named for their actions, for example, B cell–differentiating factor, or B cell–stimulating factor 2. However, the nomenclature has since been rationalized by international agreement to that of the interleukins. For example, the name of B cell–differentiating factor was changed to interleukin-4. A number of cytokines selected for their biologic and clinical relevance are listed in Table 1, but it would be beyond the scope of this text to list all cytokines, which now number more than 100.
Table1. Examples of cytokines and their clinical relevance.
Many of the receptors for cytokines and hematopoietic growth factors (see above), as well as the receptors for prolactin, and growth hormone are members of a cytokine-receptor superfamily that has three subfamilies (Figure1). The members of subfamily 1, which includes the receptors for IL-4 and IL-7, are homodimers. The members of subfamily 2, which includes the receptors for IL-3, IL-5, and IL-6, are heterodimers. The receptor for IL-2 (and several other cytokines) consists of a heterodimer plus an unrelated protein, the so-called Tac antigen. The other members of subfamily 3 have the same γ chain as IL-2R. The extra cellular domain of the homodimer and heterodimer subunits all contain four conserved cysteine residues plus a conserved Trp-Ser-X-Trp-Ser domain, and although the intracellular portions do not contain tyrosine kinase catalytic domains, they activate cytoplasmic tyrosine kinases when ligand binds to the receptors.
Fig1. Members of an important cytokine receptor superfamily, showing shared structural elements. Note that all subunits except the α subunit in subfamily 3 have four conserved cysteine residues (C) and a Trp-Ser-X-Trp-Ser motif (X). Many subunits also contain a critical regulatory domain in their cytoplasmic portions (R). CNTF, ciliary neurotrophic factor; Epo, erythropoietin; GH, growth hormone; LIF, leukemia inhibitory factor; OSM, oncostatin M; PRL, prolactin.
The effects of the principal cytokines are listed in Table 1. Some of them have systemic as well as local paracrine effects. For example, IL-1, IL-6, and tumor necrosis factor-α cause fever, and IL-1 increases slow-wave sleep and reduces appetite.
Another superfamily of cytokines is the chemokine family. Chemokines are substances that attract neutrophils (see previous text) and other white blood cells to areas of inflammation or immune response. Over 40 have now been identified, and it is clear that they also play a role in the regulation of cell growth and angiogenesis. The chemokine receptors are G-protein–coupled receptors that cause, among other things, extension of pseudopodia with migration of the cell toward the source of the chemokine.
