Actions of cytokines on the immune response and viral interactions: An overview

The central role of cytokines includes cell-to-cell comthe activity of leukocytes, or facilitate communication between different leukocytes. The molecule must also munication, inflammatory response amplification, and immune response regulation. This review will outline be characterized fully at the protein and DNA levels. Thus, all interleukins are cytokines, but some cytothe general actions of cytokines in inflammatory and immune responses and the mechanisms by which viral kines are not interleukins, because they are not products of leukocytes. Cytokines can either synergize or infections can evade these host defenses. Because of the multiple different systems in which antagonize other cytokines. These cytokine interactions lead to a cascade of functions. Cytokines bind cytokines have been investigated, the nomenclature is confusing; the same cytokines have multiple names to specific receptors on the cell surface. Most cytokine receptors are two-chained polypeptides. Cytokines can based on their biological response. Thus, the term cytokine has been designated to include mediators secreted mediate cell-to-cell communication which is separate from, or in addition to, contact-mediated cell-cell comby lymphocytes (lymphokines) and monocytes (monokines), as well as products of other cells involved in cell munication. The most important cytokines with respect to the liver are the IFNs, IL-1, IL-6, and tumor necrosis communication. Cytokines are generally small, single polypeptides approximately 20 kd in size and are charfactor (TNF). acterized by their transient production. Their synthesis is transcriptionally regulated, with cytokine mesCYTOKINE SIGNALING senger RNA (mRNA) generally being very short-lived. In recent years, there has been a veritable explosion Their structures are simple and their biological activiof information about how cytokines signal their effects ties are characterized by pleiotropism, i.e., they have within cells. It was known that after cytokines bind to multiple different actions on a variety of cells, with a their receptors, they rapidly induce effects. However, redundancy of activities between cytokines. For examit was not known how this was accomplished. It is now ple, interleukin 6 (IL-6) was given diverse names, declear that there are common pathways for second-mespending on the assay in which it was discovered, insenger signaling. These pathways, which were first decluding interferon (IFN)-b2, hepatocyte growth factor, scribed for interferon alfa (IFN-a), have been shown and plasma cell growth factor. While each name corfor many other cytokines and are outlined below. rectly identified one action of IL-6, it did not suggest First, the cytokine binds to its receptor. Each cytothe wider functions we now ascribe to the interleukin. kine receptor has a specific chain (usually named a The interleukin designation also has been introduced chain) which binds to the ligand; the other chain is to simplify confusing nomenclature. To be designated required for high-affinity binding and signaling and an interleukin, a molecule must be the product of leumay be shared with other cytokine receptors. The rekocytes and must either regulate cell growth, and/or ceptor usually is comprised of two or three chains. Binding of ligand brings the receptor chains into apposition. Many cytokine receptors share common chains Abbreviations: mRNA, messenger RNA; IL, interleukin; IFN, interferon; (e.g., IL-2 receptor shares a common g chain with reTNF, tumor necrosis factor; JAKs, Janus-activated kinases; STATs, signal ceptors for IL-7, IL-9, and IL-15). Cytokines which transducers and activators of transcription; GAS, g-activated site; HLA, hushare common receptor chains often have similar funcman lymphocyte antigen; NK, natural killer; ISGF, interferon-stimulated gene factors; ISRE, interferon-stimulated response elements; 2*5*-OAS, 2*5*-olitions. goadenylate synthetase; GAF, g-activated factor; Ig, immunoglobulin; GMFigure 1 compares the signaling mechanisms of three CSF, granulocyte-macrophage colony stimulating factor; DTH, delayed type cytokines: IFN-a, IFN-g, and IL-6. After dimerization hypersensitivity; LPS, lipopolysaccharide; HBV, hepatitis B virus. of the receptor with binding to ligand, tyrosine kinases From the Department of Medicine and Molecular Microbiology, Washington are activated. These tyrosine kinases are associated University School of Medicine, St. Louis, MO.