Cytokines in Innate Immunity

lnterferon-a and 13, Families. Type I interferons are composed of two subgroups. The interferon-a family consists of approximately 20 different proteins with an average molecular mass of 20 kDa. Structurally dissimilar interferon^ is a single protein.

Termination of viral infections is the major function of IFN-a and B. In the context of host defense, IFN-a and B serve four functions: (1) they initiate the production of 2'3'-oligoadenylate synthase that interferes with the replication of both DNA and RNA, (2) they prevent synthesis of essential amino acids such as tryptophan, (3) they augment and accelerate the autolytic activity of NK cells, and (4) they upregulate MHC I expression and enhance the CTL response.

TumorNecrosis Factor-a. TNF-a is a 17-kDaprotein produced by mononuclear phagocytes and T cells following exposure to bacterial endotoxins. It is unusual in that the molecular orientation is reversed. The amino acid terminus and the transmembrane fractions are within the membrane. The C-terminus is extracellular. Enzymatic cleavage of surface-bound TNF-a creates fragments that circulate in the blood. These fragments form a trimeric 5 1-kDa B-strand "jelly roll" (Gruss and Dower, 1995). The homotrimers bind to two different receptors, p75 or p55, which are members of the TNF type III receptor family.

At low (10-9 M) concentrations, TNF acts in an autocrine and paracrine fashion. It helps to terminate viral infections by increasing the expression of MHCI molecules and the CTL response to infected cells. In bacterial infections, TNF increases the killing activity of neutrophils and the production of IL-1, IL-6, and TNF. To a lesser extent, TNF acts on other phagocytes (Havell, 1992).

TNF also upregulates the endothelial cell expression of adhesion molecules. The upregulation of the adhesion factors promotes localization of neutrophils, monocytes, and lymphocytes in areas of inflammation.

At moderate levels, TNF acts as endogenous pyrogen stimulating the hypothalamus to induce fever. The fever induction is often augmented by TNF-induced IL-1 and IL-6 production. In addition, TNF acts on the liver inducing the production of acute-phase proteins such serum amyloid A, C-reactive protein, anda2-macroglobulin. The production of acute-phase proteins reduces the activity of proteases and tissue injury.

In high concentrations, TNF acts as endocrine hormone causing tissue injury, intravascular coagulation, and shock. At concentrations approaching 10-7 M, animals usually die of circulatory collapse.

Circulatory collapse is induced by several different mechanisms. Using the nitric oxide synthase enzyme, TNF induces the production of NO that decreases myocardial contractibility. Relaxation of smooth muscle and vascular tone further depresses blood pressure and tissue perfusion. Finally, TNF shifts the activity of procoagulants and the upregulation of endothelial adhesion factors. Both factors induce clotting and the occlusion of blood vessels by neutrophils attaching to the endothelium (Beutler and Grau, 1993).

Interleukin 1. IL-1 is comprised of two polypeptides each having a molecular mass of 17 kDa. IL-la and IL-1 B are the products of two genes and have less than 30% homology to each other (Conti, 1991). Most of the IL-1 is synthesized by macrophages and keratinocytes (Kupper, 1988) activated by endotoxin, TNF, or macrophage cytokines (Krakauer, 1986). Synthesis of IL-1 by keratinocytes provides a mechanism for inflammatory responses in local areas devoid of macrophages.

IL-1 precursors are 33-kDa proteins cleaved by an endogenous protease to the biologically active 17-kDa form. IL-lfi is often found in the circulation after gram-negative sepsis; thus, IL-lfi acts as an endocrine hormone. IL-1 binds to receptors that are members of the Ig superfamily. The type I receptor binds IL-lfi, whereas the type II receptorbinds IL-la (Conti, 1991).

The effects of IL-1 are concentration dependent. At low concentrations, IL-1 mediates inflammatory responses similar to TNF. It causes upregulation of MHC I, initiation of coagulation, and increased leukocyte adhesion in the vasculature (O'Garra, 1989a,b). At high concentrations, IL-1 acts as an endocrine hormone that causes fever, synthesis of acute-phase proteins, and metabolic wasting.

Interleukin 6. IL-6 is produced by mononuclear phagocytes, endothelial cells, fibroblasts, and IL-l-stimulated T cells. The IL-6 homodimer is a single gene product of 26 kDa.

Normally, this cytokine binds to a dimeric receptor consisting of a 60-kDa binding protein with the WSXWS motif and a 130-kDa signal transduction protein. The gpl30 receptor binding protein is shared by IL-6, IL-11, leukemia inhibitory factor, oncostatin M, ciliary neurotropic factor, and cardiotropic 1. Stimulation of cells with IL-6 causes dimerization of the gpl30 protein, activation of intracellular kinases, and modification of transcription factors (Taga and Kishimoto, 1997). A nuclear factor controlling IL-6 gene expression (NF-IL-6) is also involved in the transcriptional regulation of acute-phase proteins (Kishimoto, 1992).

IL-6 has several biological functions. It causes hepatocytes to synthesize fibrinogen, an important acute-phase protein, fn addition, fL-6 may serve as an autocrine growth factor for normal and malignant B cells (e.g., plasmacytomas and myelomas) and as a costimulator for T cells and thymocytes. Some data also suggest that IL-6 serves as a cofactor for the growth of hematopoietic stem cells (Kishimoto, 1992).

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