What are cytokines?
Cytokines are small, water-soluble, signaling proteins and glycoproteins secreted by hematopoietic and non- hematopoietic cells of the immune system, such as macrophages, lymphocytes, neutrophils, basophils, and eosinolphils. The molecular weights of cytokines range from 8 to 80 kDa, and many of them are found to be biologically active in their oligomeric forms. Once the cytokines are produced within the cytoplasm of the cells, they are secreted and present in the tissue extracellular fluid (ECF). Cytokines are a category of signaling proteins, like hormones and neurotransmitters, and function as chemical communicators between cells. They are responsible for regulating a variety of immunological and inflammatory responses during host defense against pathogen.
Fig. 1 Cytokines.
The signal transduction process is initiated from the binding of cytokines to their specific receptors on the surface of target cells and coupled to subsequent cascades of intracellular signaling via second messengers, often tyrosine kinases, to alter the cell functions. Generally, the binding of one cytokine to its cell-surface receptor can stimulate the release of many other cytokines. The released cytokines can have effect via autocrine, if they act on the cell that secretes them; paracrine, if the target cell is in the vicinity of their secretion; or endocrine, if they diffuse to distant regions of the body. Many cytokines can modulate the synthesis or the actions of other cytokines in a complex network of interactions.
During innate and adaptive immunity, they potentiate cellular communication via autocrine and paracrine mechanisms. In response to injury/infection, cytokines are secreted by inflammatory cells over several hours to days, and in some instances even weeks.
Proinflammatory cytokines and anti-inflammatory cytokines
Cytokines can be classified based on functional classes. The current work references cytokines based on broad categories of proinflammatory or anti-inflammatory outcomes.
Cytokines acting in a proinflammatory manner worsen some disease by producing fever, inflammation, and tissue destruction. However, proinflammatory cytokines also recruit immune factors that, while increasing inflammation, can resolve infection. Classic proinflammatory cytokines include but not limited to interleukin (IL)-1α, IL-1β and IL-17A, tumor necrosis factor (TNF)-α, and interferon (IFN)-γ.
Anti-inflammatory cytokines act to control the proinflammatory response through receptor antagonism, inhibition of cytokine synthesis, and regulation of immune cell activation. Common anti-inflammatory cytokines include IL-1 receptor antagonist (IL-1RA), IL-4, IL-10, and transforming growth factor (TGF)-β.
Cytokines and cancer
Cytokines are small proteins, secreted by both immune and tumor cells, that regulate diverse processes including survival, growth, and differentiation. The IL-6 family of cytokines which includes IL-6, Oncostatin M (OSM), leukemia inhibitory factor (LIF), IL-11, ciliary neurotrophic factor, cardiotrophin-1, interleukin-27, and cardiotrophin-like cytokine has been implicated in normal breast development, most importantly during involution, and are often dysregulated in breast cancer. Each IL-6 family member binds to a ligand specific receptor and the gp130 receptor, activation of gp130 results in the phosphorylation of multiple tyrosines via JAK family members, and activation of STAT3. In addition, gp130 signaling also promotes the activation of the protein tyrosine phosphatase (SHP2) and activation of the MAPK signaling cascade as well as the PI3K/AKT pathway124. Phosphorylation on Y759 of gp130 is necessary for the activation of SHP2, while phosphorylation of Y767, Y814, Y905, and Y915 is needed in order for STAT3 to become activated. All three of these pathways have been found to be activated in human breast cancer tissues
TGF-β is a cytokine that is involved in a variety of cellular processes and has both tumor suppressing and tumor promoting activities. Activation of the TGF-β receptor leads to initiation of downstream signaling through the phosphorylation of SMAD (mothers against DPP homologs (Drosophila)) proteins, a family of transcription factors. Growth inhibition occurs via the induction of CDK inhibitor proteins and repression of c-MYC expression. The ability of TGFβ to inhibit tumor growth is often associated with lower tumor stage and growth promotion is associated with advanced tumor stage and metastasis. Tumors which have disabled the growth inhibitory arm of TGF-β signaling allow TGF-β to enhance cell invasion, migration, and evade the immune system, thereby promoting tumor growth. Cipriano et al. observed that activated RAS induced a p16- and p53-independent senescence in HMECs mediated by TGFβ signaling (Cipriano et al. in prep).
The evolution and production of cytokines
Cytokines are small, secreted proteins that have a specific effect on the interaction, communication, or behavior of cells. Although putative cytokines have been identified in many invertebrates species, including Spatzle and Unpaired in Drosophila and Insect chemotactic peptide in the moth, the majority of cytokines utilized by modern day vertebrates most likely evolved after the split from invertebrate lineages, coincident with the development of adaptive immunity. Proinflammatory cytokines, such as interleukin (IL)-17A and interferons, evolved early during the evolution of lower vertebrates, while regulatory and immunosuppressive cytokines, such as IL-4 and IL-10, are thought to have evolved more recently. In vertebrates, cytokines play a pivotal role in the maintenance of homeostasis and in the coordination of innate and adaptive immune responses.
Much of the work on cytokines has focused on the production of these proteins by specialized subsets of CD4+ T cells that play a pivotal role in the coordination of immunity. These CD4+ T cell subsets, called Th1 cell, Th2 cell, and Th17 cell, are defined by their production of unique combinations of cytokines and participation in distinct immunological programs. Specifically, Th1 cells produce the signature cytokine IFN-γ and are involved in immunity to intracellular pathogens, Th2 cells produce IL-4, IL-5 and IL-13 and participate in control of helminth infection, and Th17 cells produce IL-17A and IL-17F and are important for immunity to extracellular pathogens such as bacteria and fungi. Dysregulation of either of these CD4+ T cell subsets can be detrimental to the host, as Th1 cells can be associated with organ specific autoimmunity, Th2 cells are linked to the development of allergy and asthma, and Th17 cells appear to play critical roles in the development of multiple autoimmune diseases including inflammatory bowel disease, multiple sclerosis, and arthritis. Although much of the work aimed at elucidating the features of these three immune programs has focused the role of CD4+ T cells, it is becoming apparent that cells of the innate immune system also play a crucial part in these responses and are important sources of the cytokines associated with each type of immunity.