Cytokine

Cytokines are a loosely defined group of small proteins, typically between 5 and 25 kDa in size, that play a key role in cell signaling. Many different cell types produce them, including immune cells, endothelial cells, fibroblasts, and various connective tissue cells. A single cytokine can be made by more than one kind of cell. Because they are generally too large to cross cell membranes, cytokines work by binding to specific receptors on the surface of their target cells. This category includes chemokines, interferons, interleukins, lymphokines, and tumor necrosis factors, though hormones and growth factors are usually not counted as cytokines, even if the terminology sometimes overlaps.

Cytokines are especially important in the immune system, where they influence immune responses and inflammation. They help balance humoral and cell-based immunity, and they regulate how certain cell populations mature, grow, and respond to signals. Some cytokines can boost or suppress the effects of other cytokines in complicated ways. Compared to hormones, cytokines are generally released at lower concentrations. When one cell releases an immune cytokine, the signal can act on the same cell (autocrine signaling), on nearby cells (paracrine signaling), or on cells throughout the body (endocrine signaling).

**Terminology and nomenclature**

The word “cytokine” comes from ancient Greek: *cyto* (from *kytos*, meaning “cavity” or “cell”) and *kines* (from *kinēsis*, meaning “movement”). Historically, cytokines were classified as lymphokines, interleukins, or chemokines based on which cell type secreted them, what they did, or which cells they targeted. However, because cytokines often show considerable redundancy and pleiotropism, these categories are now considered outdated, with many exceptions. The term “interleukin” was originally used for cytokines thought to mainly target white blood cells (leukocytes); today it is mostly used to name new cytokine molecules and has little to do with their actual function. Most interleukins are produced by T-helper cells. Other older terms include lymphokines (from lymphocytes), monokines (from monocytes), interferons (involved in antiviral responses), colony stimulating factors (which support cell growth in semisolid media), and chemokines (which mediate chemoattraction between cells).

**Classification**

*Structural*: Some cytokines can be grouped by their three-dimensional structure. The four-α-helix bundle family includes members with a bundle of four α-helices and is divided into three subfamilies: the IL-2 subfamily (the largest, containing non-immunological cytokines like erythropoietin and thrombopoietin, and split into long-chain and short-chain types), the interferon subfamily, and the IL-10 subfamily. The IL-1 family mainly includes IL-1 and IL-18. The cysteine knot cytokines include members of the transforming growth factor beta superfamily (such as TGF-β1, TGF-β2, and TGF-β3). The IL-17 family is not yet fully characterized, but its members promote the proliferation of cytotoxic T-cells.

*Functional*: A more practical classification for clinical and experimental work divides immunological cytokines into type 1 (which enhance cellular immune responses, e.g., TNF, IFN-γ) and type 2 (which enhance antibody responses, e.g., TGF-β, IL-4, IL-10, IL-13). Cytokines from one subset tend to inhibit those from the other. Dysregulation of this balance is being studied for its possible role in autoimmune disorders. Several inflammatory cytokines are triggered by oxidative stress, and because cytokines themselves can release other cytokines and increase oxidative stress, they are important in chronic inflammation, fever, and the production of acute phase proteins in the liver (e.g., IL-1, IL-6, IL-12, IFN-α). Cytokines also participate in anti-inflammatory pathways and are being explored as treatments for pathological pain from inflammation or nerve injury, with both pro-inflammatory and anti-inflammatory types regulating these processes.

**Difference from hormones**

Classic hormones circulate in nanomolar concentrations (10⁻⁹ M) that usually vary by less than tenfold. In contrast, some cytokines, like IL-6, circulate in picomolar concentrations (10⁻¹² M) that can increase up to a thousand times during trauma or infection. Another difference is that cytokines come from many cellular sources—virtually all nucleated cells, especially endothelial, epithelial, and resident macrophages, can produce IL-1, IL-6, and TNF—while classic hormones like insulin are secreted from discrete glands such as the pancreas. The current terminology treats cytokines as immunomodulating agents. However, distinguishing them from hormones is complicated because some cytokine effects are systemic (affecting the whole organism) rather than just local. For example, cytokines can act in autocrine, paracrine, or endocrine ways (such as when they act as pyrogens). Essentially, cytokines are not limited to their immunomodulatory role.

**Receptors**

In recent years, the study of cytokine receptors has expanded, but the source text does not provide further details beyond this opening phrase.