Secreted Growth Factors and Cytokines
Growth factors and cytokines are protein molecules that function in signaling in the body, and they play an important role in various physiological activities, such as cell communication, immune function and embryogenesis. Cytokines are produced by a variety of hematopoietic and non-hematopoietic cell types and, like hormones, can spread to the site of action through autocrine, paracrine, and endocrine pathways. Many cytokines have growth factor activity, which in some cases stimulates growth, while in others it regulates metabolism and/or cell homeostasis. Different tissues secrete different cytokines according to their functional characteristics. For example, adipose tissue secretes more than 50 different homeostasis regulatory proteins. Skeletal muscle can synthesize and secrete several homeostasis regulatory peptides and proteins called actin.
Secreted Growth Factors
Growth factors are a class of proteins that stimulate the growth of specific tissues and play an important role in promoting cell differentiation and cell division. According to its source, growth factors can be divided into three major categories of microbial, plant and animal origin. The growth factors that scientists originally obtainedin vitro were isolated from animal tissues including mice and cattle. Examples include insulin-like growth factors (somatomedins), which stimulate growth by mediating growth hormone secretion by the pituitary; epidermal growth factors, which stimulate the growth of epithelial cells; platelet-derived growth factors, which stimulate the growth of muscle cells and connective tissue cells; and Nerve growth factor, which stimulates the growth of neuronal cells. A growth factor that is commonly distributed in plants, animals, and microorganisms is lipoic acid, which is used for photosynthesis and metabolism of lipids and carbohydrates. In addition, some cytokines also have growth factor activity. Growth factors are mainly divided into the following families：
- Platelet-Derived Growth Factor Family (PDGF). PDGF is the main protein growth factor in human serum, is a significantly thermally stable cationic protein, is composed of two related but different polypeptide chains and can play a role in the development of certain human cancers.
- Vascular Endothelial Growth Factor Family (VEGF). VEGF was originally isolated from the conditioned medium of follicular stellate and bovine pituitary follicular cells, which can stimulate angiogenesis and increase capillary permeability to different macromolecules.
- Epidermal Growth Factor Family (EGF). EGF is composed of 53 amino acids bound by three internal disulfide bonds. Its members, such as TGF-α, have a sequence similarity in amphoteric regulatory proteins. When bound to the correct receptor, it shows a mitotic effect on EGF-responsive cells.
- Fibroblast Growth Factor Family (FGF). FGF contains an expanding multi-gene family that exhibits mitotic activity against a variety of mesenchymal, neuronal, and epithelial-derived cells.
- Insulin Family. Major in vivo functions involve the regulation of rapid anabolic responses, such as glucose uptake, adipogenesis, and amino acid and ion transport. In addition, insulin can stimulate DNA synthesis and cell growth.
- Hepatocyte Growth Factor (HGF). It is isolated from plasma or platelets and is considered to play an important role in liver regeneration.
- Neurotrophin Family (NGF). NGF can mediate cellular interactions and regulate the survival of neurons during adult nervous system development and function.
Classification of Cytokines
- Interleukins (ILs)
Leukocytes can secrete cytokines to stimulate humoral and cellular immune responses and the activation of phagocytes. The cytokines secreted by lymphocytes are called lymphokines, while the cytokines secreted by monocytes or macrophages are called single factors. Some lymphokines are also called ILs, they are not only secreted by white blood cells, but also can affect the cellular response of white blood cells. New ILs are constantly being discovered and identified. The more common ones are:
| ILs | Principal Source | Primary Activity |
|---|---|---|
| IL1-α and -β | macrophages and other antigen-presenting cells (APCs) | co-stimulation of APCs and T cells, inflammation and fever, acute phase response, hematopoiesis |
| IL-2 | activated Th1 cells, NK cells | proliferation of B cells and activated T cells, NK functions |
| IL-3 | activated T cells | growth of hematopoietic progenitor cells |
| IL-4 | Th2 and mast cells | B cell proliferation, eosinophil and mast cell growth and function, IgE and class II MHC expression on B cells, inhibition of monokine production |
| IL-5 | Th2 and mast cells | eosinophil growth and function |
| IL-6 | activated Th2 cells, APCs, other somatic cells such as hepatocytes and adipocytes | acute phase response, B cell proliferation, thrombopoiesis, synergistic with IL-1β and TNF on T cells |
| IL-7 | thymic and marrow stromal cells | T and B lymphopoiesis |
| IL-8 | macrophages, other somatic cells | chemoattractant for neutrophils and T cells |
- Adipokines
In addition to esterifying fatty acids into glycerine to store excess carbon in the body, mature fat cells have the ability to synthesize and secrete enzymes, growth factors, cytokines, and hormones that are associated with an organism's overall energy homeostasis. Recent studies have shown that many factors secreted by adipocytes are pro-inflammatory mediators. These proteins are called adipokines, including TNF-α, IL-6 and leptin. The following table lists some protein factors that affect overall metabolic homeostasis and regulate the inflammatory process, some of which are not specific to adipose tissue.
| Factors | Principal Source | Major Actions / Comments |
|---|---|---|
| adipsin | adipocytes, liver, monocytes, macrophages | rate limiting enzyme in complement activation |
| apelin | adipocytes, vascular stromal cells, heart | levels increase with increased insulin, exerts positive hemodynamic effects, may regulate insulin resistance by facilitating expression of brown adipose tissue (BAT) uncoupling proteins |
| chemerin | adipocytes, liver | modulates expression of adipocyte genes involved in glucose and lipid homeostasis such as GLUT4 and fatty acid synthase |
| C-reactive protein (CRP) | hepatocytes, adipocytes | modulates endothelial cell functions by inducing expression of various cell adhesion molecules |
| omentin | visceral stromal vascular cells of omental adipose tissue | the omentum is one of the peritoneal folds that connects the stomach to other abdominal tissues, enhances insulin-stimulated glucose transport |
| monocyte chemotactic protein-1 (MCP-1) | leukocytes, adipocytes | recruits monocytes, T cells, and dendritic cells to sites of infection and tissue injury |
| vaspin | visceral and subcutaneous adipose tissue | levels decrease with worsening diabetes, increase with obesity and impaired insulin sensitivity |
- Hepatokines
The main function of the liver is to produce multiple proteins that circulate in the vasculature and perform multiple functions. Protein factors secreted from the liver have important regulatory effects on overall lipid and glucose homeostasis. Many liver factors are not unique to the liver, and can also be expressed and secreted from other tissues, such as some adipokines and actin that have been identified：
| Factors | Principal Source | Major Actions / Comments |
|---|---|---|
| angiopoietin-like 6 (ANGPTL6) | hepatocytes | functional ANGPTL6 is associated with lean body mass, protection from obesity, and enhanced insulin sensitivity |
| C-reactive protein (CRP) | hepatocytes, adipocytes | assists complement interaction with foreign and damaged cells; enhances phagocytosis by macrophages; levels of expression regulated by circulating IL-6 |
| fetuin A (AHSG) | hepatocytes | member of the family of liver produced and secreted binding proteins that function as cargo transporters in the blood |
| fetuin B | hepatocytes | encoded by FETUB gene; reduces glucose effectiveness |
| fibrinogen-like protein 1 | hepatocytes | encoded by the FGL1 gene; functions as a hepatocyte growth factor involved in liver regeneration |
| selenoprotein P (SELPP) | hepatocytes | major selenium transport protein; increased circulating levels associated with insulin resistance; expression reduced in response to insulin |
| serum hormone binding globulin (SHBG) | hepatocytes; also brain, uterus, testes, placenta | normally binds androgens and estrogen in plasma; high circulating levels protect from type 2 diabetes development; reduced levels associated with increased risk for cardiovascular disease |
- Myokines
Skeletal muscle can also produce and secrete a large number of proteins and peptides that play autocrine, paracrine, and endocrine functions, collectively referred to as actin:
| Factors | Principal Source | Major Actions / Comments |
|---|---|---|
| angiopoietin 1 (ANGPT1) | cardiac myocytes, smooth muscle | promotes muscle growth and homeostasis; prevents insulin resistance |
| brain derived neurotrophic factor (BDNF) | cardiac myocytes; smooth muscle; various brain regions | increased β-oxidation of fatty acids; increased glucose oxidation; enhances neurogenesis in the brain improving cognition and spatial memory |
| FGF21 | hepatocytes, adipose tissue, myocytes, pancreas, duodenum | increases fat utilization and energy expenditure, reduces body weight, reduces whole-body fat mass, reduces lipid content in hepatocytes |
| IL-15 | monocytes, thyroid, lymph nodes, myocytes | enhances muscle hypertrophy; enhances fatty acid β-oxidation and thermogenesis in brown adipose tissue (BAT) |
| musclin | skeletal muscle | expression of the OSTN gene stimulated by insulin; production and secretion stimulated by exercise to promote exercise tolerancevia enhanced oxidative phosphorylation |
| myostatin | skeletal muscle | enhances glucose and fatty acid oxidation in skeletal muscle; involved in muscle growth and overall homeostasis |
| myonectin | skeletal muscle | functions as a nutrient responsive regulator of total body fatty acid metabolism |
