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Understanding Cytokines and Cell Communication
By: Michael Q. Pugliese and Peter T. Pugliese, MD
Posted: October 31, 2013, from the November 2013 issue of Skin Inc. magazine.
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IL-3 is a cytokine that was initially shown to activate mast cells and induce the proliferation of hematopoietic stem cell lines. Human keratinocytes also have been shown to release an IL-3like cytokine, which enhances the activity of natural killer cells, and stimulates the release of oxygen radicals by granulocytes. However, human keratinocyte IL-3 appears to be distinct from T-cell IL-3. The exact nature of this cytokine remains to be clarified by sequence analysis and gene cloning. Through the production of these cytokines with IL-3like capacity, keratinocytes may participate in the regulation of the activity of different hematopoietic cells, thereby turning on early nonspecific host defense mechanisms against transformed cells and various harmful microbial organisms. These cytokines could be good guys or bad guys, depending on the biological circumstances.
Platelet-derived growth factor (PDGF)
PDGF was the first of the numerous growth factors identified that regulate cell growth and division. It has a significant role in blood vessel formation, called angiogenesis, and the growth of blood vessels from already-existing blood vessel tissue. Uncontrolled angiogenesis is characteristic of the prominent veins seen in rosacea clients. At the extreme, squamous and basal cell carcinoma are examples of excessive blood vessel growth. PDGF is a potent mitogen (causes cell division) for cells such as smooth muscle cells and glial cells, which arise from mesenchymal tissue. PDGF is synthesized, stored and released by platelets—small cells that are involved in blood-clotting—upon activation. This is where it derives its name; however, PDGF is produced by many types of cells, including smooth muscle cells, activated macrophages and endothelial cells. PDGF, along with certain other factors, is able to modulate the activity of epidermal growth factor, an important skin cytokine.
Epidermal growth factor (EGF)
Activation of EGF produces cellular proliferation, differentiation and cell survival. EGF is a low-molecular-weight polypeptide found in many human tissues, including the submandibular gland and the parotid gland. It is genetically engineered from a variety of bacterial organisms, which are killed, and the EGF is extracted. The biological effects of salivary EGF include healing of oral and gastroesophageal ulcers, inhibition of gastric acid secretion and stimulation of DNA synthesis. EGF in the saliva provides mucosal protection from intraluminal injurious factors, such as gastric acid, bile acids, pepsin and trypsin, as well as physical, chemical and bacterial agents.
EGF binds tightly to the epidermal growth factor receptor (EGFR) on the cell surface, stimulating the intrinsic protein tyrosine-kinase activity of the receptor. The tyrosine-kinase activity, in turn, initiates a signal transduction cascade that results in three main biochemical changes within the cell, which include a rise in intracellular calcium levels, increased glycolysis and protein synthesis. Increased tyrosine-kinase activity elevates the expression of certain genes, including the gene for EGFR that ultimately leads to DNA synthesis and cell proliferation.
The actions of cytokines
Let’s look now at what a few of these cytokines do. First, a definition the various types of inflammatory response.
- Acute inflammation is marked by the classical signs in which vascular and exudative processes predominate. It has a rapid onset and generally lasts less than two weeks. These cytokines are involved in acute inflammation: PDGF, VEGF, TNF, IL-1α, IL-1β, IL-6, IL-11, IL-16 and IL-8.
- Chronic inflammation is prolonged and persistent inflammation marked chiefly by new connective tissue formation. It may be a continuation of an acute form or a prolonged low-grade fever. Characterized by slow onset, it lasts at least a month. These cytokines are associated with the initiation and persistence of chronic inflammation: IL-2, IL-3, IL-6, IL-7, IL-8, IL-9 IL-12, IL-14, IL-15, TGA-α, TGF-β1 and TGF-β2.
- Subacute inflammation is an intermediate condition between chronic and acute inflammation, exhibiting some of the characteristics of each. It can last between three and four weeks. These cytokines are the good guys and are anti-inflammatory: TGF-β3, IL-4, IL-5, IL-10, IL-11, IL-13, IL-16, Wisp-2 and HGF.