Interleukin-18

Interleukins (from Latin/Greek inter = between; leukos = white; kinein = to move) are a group of endogenous, short-chain regulatory proteins (cytokines) of the immune system (IL1-IL38). Interleukins are mediators for the induction, progression and control of T-cell-mediated cytotoxic immune reactions and B-cell activation (antibody production). They are mainly produced and secreted by stimulated leukocytes, monocytes and macrophages. To date, around 38 different interleukins have been clearly identified. Each cytokine of the interleukin group is assigned a nomenclatural number for its classification (IL-1 to IL-38).

Some structurally related substances have been grouped into families. Their members often have a similar function or are involved in the fine regulation of immune reactions, for example by regulating the synthesis of related interleukins.

Interleukin-18, which belongs to the same cytokine family as IL-1beta, is a proinflammatory cytokine that belongs to the interleukin-1 cytokine superfamily and has important functions in acute or chronic inflammation. The cytokine has functional similarities to interleukin-12 and is a regulator of natural and acquired immunity. Interleukin-18 is encoded by a gene localized on chromosome 11 (11q22.2-q22.3). Interleukin-18 has no pyogenic activity.

Interleukin-18 is produced by different cell systems such as macrophages, dendritic cells, fibroblasts, keratinocytes, osteoblasts, intestinal epithelial cells, Kupffer's stellate cells, microglial cells and adrenocortical cells.

The bioactive form of interleukin-18 is transferred from an inactive 24 kDa preleukin into its bioactive 18 kDa form by a protease, the interleukin-1 converting enzyme protease (also known as caspase-1 - see caspases below).

Interleukin-18 initiates its biological effect via the specific receptor complex(IL18R1 and IL18RAP). The production of both Th1 and Th2 cytokines can be stimulated via this receptor complex. This receptor complex is expressed by macrophages, neutrophil granulocytes, NK cells, endothelial cells, keratinocytes, melanocytes and smooth muscle cells.

Interleukin-18 can be detected at elevated levels in synovia of patients with rheumatoid arthritis.

Interleukin-18 induces the formation of interferon gamma, interleukin-2 and GMCSF in NK cells and other T lymphocytes after their activation by microbial products (e.g. by lipopolysaccharides). In the production of interferon gamma, but not of GMCSF and interleukin-2, interleukin-12 acts synergistically. Interleukin -18 is additive in the activation and proliferation of T lymphocytes and NK cells initiated by interleukin-2. This cytokine network, interleukin-4 dependent, has been shown to inhibit IgE and IgG1 production and to activate IgG2a production in B cells.

Keratinocytes are also able to form interleukin-18. The cytokine is increased (together with interferon gamma) after UV irradiation. Melanogenesis in melanocytes is increased by interleukin-18, inhibited by interferon gamma.

Interleukin-18 is involved in a number of diseases. Hashimoto's thyroiditis, for example. It has been shown that interleukin-18 affects amyloid-beta production in neurons in Alzheimer's disease.

It has been shown that IL-18-137G/C polymorphism in various Asian populations is associated with a reduced risk of developing Alzheimer's disease.

Furthermore, the cytokine plays a role in age-related macular degeneration (AMD).

Interleukin-18 is involved in systemic juvenile idiopathic arthritis. Elevated interleukin-18 levels are associated with the development of a so-called macrophage activation syndrome (also known as hemophagocytic syndrome), a life-threatening disruption of immune system function associated with macrophage activation.

In patients with non-Hodgkin lymphoma, interleukin-18 was found to be elevated in such patients who also showed elevated LDH levels.

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