In the section on mechanisms of innate immunity, it was mentioned that various cells and complement components of innate immunity orchestrate their effects through the production of soluble mediators. These mediators include cytokines, prostaglandins, and leukotrienes. Here in this section , the role of these mediators in inflammation is outlined. A separate detailed description on cytokines is found in the section on adaptive immune response.

          Injury to tissue initiates an inflammatory response. T his response is dominated mainly by soluble mediators, referred to as cytokines. Cytokines may include inflammatory and anti-inflammatory cytokines, chemokines, adhesion molecules, and growth factors. During the innate immune response, leukocytes, such as macrophages, release a variety  of cytokines, including IL-1 and TNF-α, and IL-6. The other mediators released from activated macrophages and other cells include prostaglandins and leukotrienes. These inflammatory mediators regulate changes in local blood vessels . This begins with dilation of local arterioles and capillaries . During dilation, plasma escapes and accumulates in the area of injury. Fibrin is formed which occludes the lymphatic channels, limiting the spread of organisms.

         A second effect of these mediators is to induce changes in the expression of adhesion molecules expressed on the sur face of endothelial cells and leukocytes. Adhesion molecules (eg, selectins and integrins) cause leukocytes to attach to the endothelial cells and thereby promote their movement across the vessel wall. Thus, cells stick to the capillary walls and then migrate out (extravasation) of the capillaries in the direction of the irritant. This migration (chemotaxis) is stimulated by proteins in the inflammatory exudate, including some chemokines . A variety of cell types, including macrophages and endothelial cells, can produce chemokines. Once the phagocytic  cells migrate to the site of infection, they can initiate the engulfment of microorganisms.

            Fever is another common systemic manifestation of the inflammatory response and is a cardinal symptom of infectious disease. The main regulator of body temperature  is the thermoregulatory center in the hypothalamus.

Among the substances capable of inducing fever (pyrogens) are endotoxins of gram-negative bacteria and cytokines (eg, IL-1, IL-6, TNF-α, and the interferons) released from a variety of cells.

                The interferons (IFNs) are critical cytokines that play a key role in defense against virus infections and other intra cellular organisms, such as Toxoplasma gondii. Although the IFNs were first identified in 1957 as antiviral proteins, they are now recognized as critical immunoregulating proteins capable of altering various cellular processes, including cell growth, differentiation, gene transcription, and translation . The IFN family consists of three groups. Type I IFNs comprise numerous genes and primarily include IFN-α and IFN-β. Type II IFN consists of a single gene that produces IFN-γ. IFN-λ is a third group of IFN-like cytokines that have more recently been described. Virus infection itself triggers the production of type I IFNs. Following virus entry into a cell, the virus initiates replication and the viral nucleic acid interacts with specific microbial sensors (TLR3, TLR7, TLR 9, RIG-1, and MDA-5). This interaction triggers cellular production of IFN that is secreted from the infected cell. In contrast, the type II IFN, IFN-γ, is produced by activated NK cells in innate immune responses and by specifically sensitized  T cells in adaptive immune responses. Moreover, the cytokines IL-2 and IL-12 can trigger T cells to produce IFN-γ.

                  The IFN system consists of a series of events leading to protection of a cell from virus replication. Once the IFN is produced by the infected cell or the activated NK cell or T cell, the IFN binds to its specific cellular receptor. The IFN receptor interaction activates the JAK, STAT signaling path ways. This process triggers activation of genes that initiate production of selected proteins that inhibit virus replication. All of the IFNs share overlapping biological activities such as antiviral actions, antiproliferative actions, and immuno-regulatory actions. However, they also have unique functions that are not overlapping. For example, IFN-β is used success fully to treat patients with multiple sclerosis, whereas IFN-γ has been shown to exacerbate this disease. These potent actions of the IFNs and the advances in biotechnology are the underlying factors that have identified the clinical relevance of the IFNs. In fact, many of the IFNs have been approved by the U.S. Food and Drug Administration (FDA) for the treatment of infections, malignancies, autoimmunity, and immunodeficiency.