In the ever-evolving world of growth factors, the Cytokine class can potentially encompass nearly every single growth factor we know. Cytokines are typically small, cell-signaling proteins that are used extensively in intercellular communication. It is a family of regulators, involved in immunomodulation, hormone stimulation, hematopoiesis and embryogenesis. But scientists still disagree exactly how to properly categorize a “cytokine”. As they learn more and more about the world of growth factors vs. classic hormones, the clear-cut distinctions we're used to continue to fade away. Classic protein hormones generally circulate throughout the body in nanomolar concentrations, whereas cytokines typically circulate in the picomolar concentrations but some then magnify up to 1000-fold during trauma or infection. However, cytokines are nearly always produced by nucleated cells, whereas classic hormones are most often secreted from glands, such as the pituitary gland or the pancreas.
Two of the most studied groups of cytokines are interleukins (IL) and Colony Stimulating Factors (CSF). CSF2, often referred to as Granulocyte-Macrophage Colonly Stimulating Factor (GM-CSF), is very closely associated with IL3 and IL5. While there is no significant amino acid sequence homology between the three, they exhibit a number of biological similarities. For instance, they all contain 4 α-helices and their tertiary structures are similar. They are also closely linked on the same chromosome in both human and mice (Chromosome 5 in humans and Chromosome11 in mice). Finally, CSF2 competes with IL3 and IL5 for binding to their respective receptors (Miyajima 1993).
CSF2 has been shown to be an integral signal factor (along with IGF-1, IL1 and activin) produced in the preimplantation development in a number of mammals, including humans, mice, pigs and cows. Treatment with CSF2 in cows during in vitro fertilization was able to significantly reduce pregnancy loss and enhanced embryonic compentence for posttransfer survival (Loureiro 2009). The lack of CSF2 in knockout mice have shown smaller birth size, fetal growth retardation, and increased mortality within the first 3 weeks.
CSF2 has also been tested in a recent phase II trial as an adjuvant treatment for post-pancreatic cancer patients (Lutz 2011). Pancreatic cancer is the 4th leading cause of cancer-related deaths in the US and surgical removal of the pancreas remains the only viable solution to cure it. But the survival rate at 2 years post surgury remains only 42% and 5 years is only 15-20%! Lutz et al. developed an "irradiated CSF2 transfected allogeneic whole cell tumor lines for pancreas ductal adenocarcinoma immunotherapy". Lutz saw promising results over 6 months of post surgical treatment with the immunotherapy and suggested a future, multicenter phase II trial.
CSF3, also known as Granulocyte Colony Stimulating Factor (G-CSF) is a glycoprotein which stimulates bone marrow to produce granulocytes and stem cells and then to release them into the blood stream. CSF3 is commonly produced by immune cells and naturally exists in two forms, a 180 amino acid protein and the more abundant and more active 174 amino acid protein. It has also been recently implicated as being in a class of peripherally circulating peptides which have the ability to alter CNS functions and structure (Diederich, 2009). Diederich showed that CSF3 reduced apoptosis and controled the proliferation and differentiation of neural stem cells and activated several kinases (ERK1, 2 and 5) upstream of CREB (cAMP Response Element-Binding protein), indicating a prominent role in hippocampal function.
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Miyajima, A., et al. "Receptors for granulocyte-macrophage colony-stimulating factor." Blood 82 (1993): 1960-1974.
Loureiro, Bárbara, et al. "Colony-stimulating factor 2 (CSF-2) improves development and posttransfer survival of bovine embryos produced in vitro." Endocrinology 150.11 (2009): 5046-5054.
Robertson SA, Roberts CT, Farr KL, Dunn AR, Seamark RF. Fertility impairment in granulocyte-macrophage colony-stimulating factor-deficient mice. Biological Reprodution 60 (1999): 251–261
Lutz, Eric, et al. "A lethally irradiated allogeneic granulocyte-macrophage colony stimulating factor-secreting tumor vaccine for pancreatic adenocarcinoma: a phase II trial of safety, efficacy, and immune activation." Annals of surgery 253.2 (2011): 328.
Diederich, Kai, et al. "Synergetic effects of granulocyte-colony stimulating factor and cognitive training on spatial learning and survival of newborn hippocampal neurons." PloS one 4.4 (2009): e5303.
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