Chemorepulsion
Encyclopedia
Chemorepulsion is the directional movement of a cell away from a substance. Of the two directional varieties of chemotaxis, chemoattraction has been studied to a much greater extent. Only recently have the key components of the chemorepulsive pathway been illucidated. The exact mechanism is still being investigated, and its constituents are currently being explored as likely candidates for immunotherapies.
in early 2002. The phenomenon was originally referred to as "reverse chemotaxis
," and later, “fugetaxis” (derived from the latin words fugere, to flee from; and taxis, movement). For a time, the words were used interchangeably before being replaced almost exclusively by “chemorepulsion.” While "chemorepulsion" applies to all cell types, the term "immunorepulsion" is gaining momentum as a more specific term that only applies to hematopoietic blood cell types that are involved in immune responses. Different cell types to which the term "immunorepulsion" could potentially be applied include: Myeloid
lineage cells (monocytes, macrophages, neutrophils, basophils, eosinophils, erythrocytes, platelets, dendritic cells) and Lymphoid
lineage cells (T-cells, B-cells, NK-cells).
, the establishment of immune-privileged sites, and thymic emigration.
, chemokinetic agents influence the localization of neuronal cells by either attracting or repelling the growing axon
. This mechanism of context-dependent bidirectionality serves as a valuable model of chemorepulsion that can be studied in vivo. Additionally, there is growing evidence that chemorepulsion is probably a key mechanism involved in regulating leukocyte motility. Many of the chemorepellents that affect neuronal cell migration, including netrins, semaphorins, slit ligands, and ephrins have recently been implicated in the motility of immune cells. For example, the Slit protein that mediates axonal chemorepulsion has also been shown to inhibit the directed migration of leuckocytes in response to chemoattractants. Other factors might also provide chemorepulsive effects on immune cells, and these inhibitory effects might be regulated by the tissue microenvironment.
is thought to be an evolutionary adaptation to protect the most vital sensory organs and reproductive structures that would be otherwise severely impaired during an imflammatory response. Although these locations are often physically isolated or segregated from access by immune cells, there are some functionally significant characteristics of such environments that are unique, and could potentially be replicated to keep immune cells away from targeted areas. Known immunologically privileged sites include the:
Characteristics that are particular to immune-privileged sites should be seriously considered when investigating candidates for immunorepulsion therapy. These characteristics include:
due to their ability to continue developing after activation. To prevent premature instigation, it is necessary for T-cells to mature in an environment completely isolated from any potentially activating factors (antigens, cytokines, steroids, receptor antagonist
s, adhesion molecules, etc). As a result, T-cells are formed in the bone marrow
and subsequently migrate to the cortex
of the thymus
where they can mature in an antigen-free environment. The thymus supports the differentiation of multiple distinct T cell subsets that play unique roles in the immune system. For example, T-helper, T-cytotoxic, T-memory, and T-suppressor cells all develop in the thymus and must leave it to provide their functions elsewhere in the body during an immune response. In vitro models of the T-lymphopoiesis
system have revealed that the emigration of mature T-cells occurs as a result of immunorepulsion away from a chemokinetic agent generated from within the thymic organ via a G-protein coupled receptor.
response. These proteins function by modulating elements of the host:
Historically, the active sites of immunomodulatory proteins have suggested relevant targets for conventional immunotherapies. In the current paradigm, these targets also harbor potential for innovative immunorepulsion therapies.
cells leverage the chemorepulsion of immune cells to evade recognition and destruction by immune cells. Without a targeted immune response, the cancer cells can proliferate and even metastasize. Studies have been conducted to investigate which chemokines are secreted by tumors that allow them to evade response so diligently. One study showed that high expression of SDF-1 was responsible for the down-regulation of MHC class I
molecules, which significantly interferes with tumor antigen
recognition. Further investigations of high SDF-1 activity indicate that tumors eventually establish an immune privileged site through repulsion of tumor-specific lymphocytes.
Potentially clinically relevant cancer chemokines include:
Inflammation
is one of the first responses of the immune system to infection or irritation. The response is stimulated by chemical factors released by injured cells. These chemical factors induce all associated inflammatory symptoms by sensitizing pain receptors, causing vasodilation of the blood vessels at the scene, and attracting phagocytes.
Neutrophils are the first to the scene, triggering other parts of the immune system by releasing factors to summon other leukocytes and lymphocytes. Other innate leukocytes include natural killer cells, mast cells, eosinophils, basophils, macrophages, and dendritic cells. These cells function in concert by identifying and eliminating pathogens that might cause infection.
As first responders, the innate immune cells cannot afford to be specific, and must respond to foreign substances in a generic way. Neutrophils, for example, contain toxic substances in their granules that kill or hinder the expansion of pathogens. The cells attack pathogens by releasing strong oxidizing agents including hydrogen peroxide
, free oxygen radicals, and hypochlorite
. Although the attack is effective against bacteria and fungi, the response can inadvertently inflict severe damage to the surrounding host tissue. The misregulation of innate immune cells plays a key role in promulgating inflammatory conditions.
Chemorepulsion is currently being explored as a practicable therapy for the prevention or resolution of unwanted inflammatory responses. A chemorepellent functions by conveying chemical signals to immune cells that instruct them to leave or stay away from a targeted area or tissue in order to restore the tissue to a normal state.
ation medicine is to procure sustainable, site-specific unresponsiveness for the prevention of graft rejection. Current therapies achieve rejection control by indiscriminately suppressing the immune response. In this approach, any benefits achieved by immunosuppression
are overcome by increasing the patient's risk of deadly, opportunistic infections. If attainable, constitutive expression of chemorepellents by the donor tissue would create an inducible immune-privileged site for the allograft, and would be an effective alternative treatment for graft rejection prevention.
. The gradient signal of the chemokinetic agent is received through specific receptors on the cell surface and is transduced through intracellular machinery to generate the directional response. The cell moves up a gradient
of a chemoattractant or down a gradient of a chemorepellent. In addition to axon
growth cones, the model organism Dictyostelium discoideum has been instrumental in determining the mechanisms that mediate chemorepulsion and immunorepulsion. The mechanisms of gradient-sensing and cell polarization
in D.discoideum are remarkably conserved in human neutrophils.
SDF-1 rather than be attracted by lower concentrations of the same factor. Similar results have been reported for human neutrophils to the chemokine IL-8
.
In both D. discoidium and human neutrophils, there is a reversal of polarity that occurs when converting from a chemoattraction to a chemorepulsion response. Evidenced chemotaxis models have been observed using cAMP
analogs. During cAMP-mediated chemoattraction, the chemoattractant cAMP acti vates PI3K at the leading edge
along with the localized activation of the small GTPases Rac
and Cdc42
. This in turn activates PLC
which leads to the generation of IP-3, which results in a loss of PtdIns(4,5)P2 at the leading edge. The chemorepellent 8CPT-cAMP inhibits PLC activity and thereby increases Ptds(3,4,5)P3 accumulation and activation of PTEN
. In this manner, the chemorepellant reverses the polarity
of the PtdIns(3,4,5)P3 gradient and induces chemorepulsion. Recent evidence also implicates a role for PI5K and Rho
signaling during directional decision making and migration.
kinase
inhibitors, genistein and herbimycin.
| Cell Migration Glossary |
|---|
| • Chemotaxis Cellular response to an environmental substance with a directional movement. |
| • Chemokinesis Cellular response to an environmental substance with a random, non-vectorial movement. |
| • Chemoattraction Directional cell movement towards a substance |
| • Chemorepulsion Directional cell movement away from a substance |
| • Chemokines Secreted cell-signaling proteins able to induce chemotaxis in nearby cells. |
| • Immunorepulsion The active movement of immune cells away from a substance |
History and etymology
The mechanism of the chemorepulsion of immune cells was first acknowledged by medical researchers at the Massachusetts General Hospital in BostonBoston
Boston is the capital of and largest city in Massachusetts, and is one of the oldest cities in the United States. The largest city in New England, Boston is regarded as the unofficial "Capital of New England" for its economic and cultural impact on the entire New England region. The city proper had...
in early 2002. The phenomenon was originally referred to as "reverse chemotaxis
Chemotaxis
Chemotaxis is the phenomenon in which somatic cells, bacteria, and other single-cell or multicellular organisms direct their movements according to certain chemicals in their environment. This is important for bacteria to find food by swimming towards the highest concentration of food molecules,...
," and later, “fugetaxis” (derived from the latin words fugere, to flee from; and taxis, movement). For a time, the words were used interchangeably before being replaced almost exclusively by “chemorepulsion.” While "chemorepulsion" applies to all cell types, the term "immunorepulsion" is gaining momentum as a more specific term that only applies to hematopoietic blood cell types that are involved in immune responses. Different cell types to which the term "immunorepulsion" could potentially be applied include: Myeloid
Myeloid
The term myeloid suggests an origin in the bone marrow or spinal cord, or a resemblance to the marrow or spinal cord.In hematopoiesis, the term "myeloid cell" is used to describe any leukocyte that is not a lymphocyte...
lineage cells (monocytes, macrophages, neutrophils, basophils, eosinophils, erythrocytes, platelets, dendritic cells) and Lymphoid
Lymphoid
Lymphoid is a term used to describe lymph or the lymphatic system.In the context of lymphoid leukemia, it refers specifically to lymphocytes Lymphoid leukemias and lymphomas are now considered to be tumors of the same type of cell lineage. They are called "leukemia" when in the blood or marrow and...
lineage cells (T-cells, B-cells, NK-cells).
Role in physiological processes
The chemorepulsion of immune cells was first postulated a priori based on the established migratory behavior of cells evidenced in several naturally occurring physiological processes: the development of the Central Nervous SystemCentral nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
, the establishment of immune-privileged sites, and thymic emigration.
Central nervous system development
During the development of the Central Nervous SystemCentral nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
, chemokinetic agents influence the localization of neuronal cells by either attracting or repelling the growing axon
Axon
An axon is a long, slender projection of a nerve cell, or neuron, that conducts electrical impulses away from the neuron's cell body or soma....
. This mechanism of context-dependent bidirectionality serves as a valuable model of chemorepulsion that can be studied in vivo. Additionally, there is growing evidence that chemorepulsion is probably a key mechanism involved in regulating leukocyte motility. Many of the chemorepellents that affect neuronal cell migration, including netrins, semaphorins, slit ligands, and ephrins have recently been implicated in the motility of immune cells. For example, the Slit protein that mediates axonal chemorepulsion has also been shown to inhibit the directed migration of leuckocytes in response to chemoattractants. Other factors might also provide chemorepulsive effects on immune cells, and these inhibitory effects might be regulated by the tissue microenvironment.
Immune-privileged sites
Certain body tissues are able to tolerate antigens without an inflammatory immune response. Immune privilegeImmune privilege
Immune privilege is a term used to describe certain sites in the body which are able to tolerate the introduction of antigen without eliciting an inflammatory immune response. Tissue grafts are normally recognised as foreign antigen by the body and attacked by the immune system...
is thought to be an evolutionary adaptation to protect the most vital sensory organs and reproductive structures that would be otherwise severely impaired during an imflammatory response. Although these locations are often physically isolated or segregated from access by immune cells, there are some functionally significant characteristics of such environments that are unique, and could potentially be replicated to keep immune cells away from targeted areas. Known immunologically privileged sites include the:
- BrainBrainThe brain is the center of the nervous system in all vertebrate and most invertebrate animals—only a few primitive invertebrates such as sponges, jellyfish, sea squirts and starfishes do not have one. It is located in the head, usually close to primary sensory apparatus such as vision, hearing,...
and central nervous systemCentral nervous systemThe central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish... - Eyes
- PlacentaPlacentaThe placenta is an organ that connects the developing fetus to the uterine wall to allow nutrient uptake, waste elimination, and gas exchange via the mother's blood supply. "True" placentas are a defining characteristic of eutherian or "placental" mammals, but are also found in some snakes and...
and fetusFetusA fetus is a developing mammal or other viviparous vertebrate after the embryonic stage and before birth.In humans, the fetal stage of prenatal development starts at the beginning of the 11th week in gestational age, which is the 9th week after fertilization.-Etymology and spelling variations:The... - Testicles
Characteristics that are particular to immune-privileged sites should be seriously considered when investigating candidates for immunorepulsion therapy. These characteristics include:
- Low expression of Classical MHCMajor histocompatibility complexMajor histocompatibility complex is a cell surface molecule encoded by a large gene family in all vertebrates. MHC molecules mediate interactions of leukocytes, also called white blood cells , which are immune cells, with other leukocytes or body cells...
Class IA molecules. - Expression of immunoregulatory Nonclassical MHCMajor histocompatibility complexMajor histocompatibility complex is a cell surface molecule encoded by a large gene family in all vertebrates. MHC molecules mediate interactions of leukocytes, also called white blood cells , which are immune cells, with other leukocytes or body cells...
Class IB molecules. - Increased expression of surface molecules that inhibit complementComplement systemThe complement system helps or “complements” the ability of antibodies and phagocytic cells to clear pathogens from an organism. It is part of the immune system called the innate immune system that is not adaptable and does not change over the course of an individual's lifetime...
activation. - Local production of immunosuppressive cytokines, such as TGF-β
- Presence of neuropeptides.
- Expression of Fas ligandFAS ligandFas ligand is a type-II transmembrane protein that belongs to the tumor necrosis factor family. Its binding with its receptor induces apoptosis. Fas ligand/receptor interactions play an important role in the regulation of the immune system and the progression of cancer.- Structure :Fas ligand or...
that controls the entry of Fas-expressing lymphoidLymphoidLymphoid is a term used to describe lymph or the lymphatic system.In the context of lymphoid leukemia, it refers specifically to lymphocytes Lymphoid leukemias and lymphomas are now considered to be tumors of the same type of cell lineage. They are called "leukemia" when in the blood or marrow and...
cells.
Thymic emigration
T-cells are one of the most critical constituents of the adaptive immune systemAdaptive immune system
The adaptive immune system is composed of highly specialized, systemic cells and processes that eliminate or prevent pathogenic growth. Thought to have arisen in the first jawed vertebrates, the adaptive or "specific" immune system is activated by the “non-specific” and evolutionarily older innate...
due to their ability to continue developing after activation. To prevent premature instigation, it is necessary for T-cells to mature in an environment completely isolated from any potentially activating factors (antigens, cytokines, steroids, receptor antagonist
Receptor antagonist
A receptor antagonist is a type of receptor ligand or drug that does not provoke a biological response itself upon binding to a receptor, but blocks or dampens agonist-mediated responses...
s, adhesion molecules, etc). As a result, T-cells are formed in the bone marrow
Bone marrow
Bone marrow is the flexible tissue found in the interior of bones. In humans, bone marrow in large bones produces new blood cells. On average, bone marrow constitutes 4% of the total body mass of humans; in adults weighing 65 kg , bone marrow accounts for approximately 2.6 kg...
and subsequently migrate to the cortex
Cortex (anatomy)
In anatomy and zoology the cortex is the outermost layer of an organ. Organs with well-defined cortical layers include kidneys, adrenal glands, ovaries, the thymus, and portions of the brain, including the cerebral cortex, the most well-known of all cortices.The cerebellar cortex is the thin gray...
of the thymus
Thymus
The thymus is a specialized organ of the immune system. The thymus produces and "educates" T-lymphocytes , which are critical cells of the adaptive immune system....
where they can mature in an antigen-free environment. The thymus supports the differentiation of multiple distinct T cell subsets that play unique roles in the immune system. For example, T-helper, T-cytotoxic, T-memory, and T-suppressor cells all develop in the thymus and must leave it to provide their functions elsewhere in the body during an immune response. In vitro models of the T-lymphopoiesis
Lymphopoiesis
Lymphopoiesis refers to the generation of lymphocytes, one of the five different types of white blood cells , and is also more formally called lymphoid hematopoiesis.-The name Lymphopoiesis:...
system have revealed that the emigration of mature T-cells occurs as a result of immunorepulsion away from a chemokinetic agent generated from within the thymic organ via a G-protein coupled receptor.
Viral and bacterial immune evasion
Pathogens have evolved various strategies of evasion to thwart the host’s mobilization of immune cells, some of which are relevant to immunrepulsion. For example, some microbes actively seek out and infect immune-privileged tissues where the immune response is not active. Others produce immunomodulatory proteins that interfere with the host’s normal immune systemImmune system
An immune system is a system of biological structures and processes within an organism that protects against disease by identifying and killing pathogens and tumor cells. It detects a wide variety of agents, from viruses to parasitic worms, and needs to distinguish them from the organism's own...
response. These proteins function by modulating elements of the host:
- ComplementComplement systemThe complement system helps or “complements” the ability of antibodies and phagocytic cells to clear pathogens from an organism. It is part of the immune system called the innate immune system that is not adaptable and does not change over the course of an individual's lifetime...
system and inflammatoryInflammationInflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...
response - CytokineCytokineCytokines are small cell-signaling protein molecules that are secreted by the glial cells of the nervous system and by numerous cells of the immune system and are a category of signaling molecules used extensively in intercellular communication...
network - AntigenAntigenAn antigen is a foreign molecule that, when introduced into the body, triggers the production of an antibody by the immune system. The immune system will then kill or neutralize the antigen that is recognized as a foreign and potentially harmful invader. These invaders can be molecules such as...
processing and presentation pathway
Historically, the active sites of immunomodulatory proteins have suggested relevant targets for conventional immunotherapies. In the current paradigm, these targets also harbor potential for innovative immunorepulsion therapies.
Cancer immune evasion
CancerCancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
cells leverage the chemorepulsion of immune cells to evade recognition and destruction by immune cells. Without a targeted immune response, the cancer cells can proliferate and even metastasize. Studies have been conducted to investigate which chemokines are secreted by tumors that allow them to evade response so diligently. One study showed that high expression of SDF-1 was responsible for the down-regulation of MHC class I
MHC class I
MHC class I molecules are one of two primary classes of major histocompatibility complex molecules and are found on every nucleated cell of the body...
molecules, which significantly interferes with tumor antigen
Antigen
An antigen is a foreign molecule that, when introduced into the body, triggers the production of an antibody by the immune system. The immune system will then kill or neutralize the antigen that is recognized as a foreign and potentially harmful invader. These invaders can be molecules such as...
recognition. Further investigations of high SDF-1 activity indicate that tumors eventually establish an immune privileged site through repulsion of tumor-specific lymphocytes.
Potentially clinically relevant cancer chemokines include:
- IL-8Interleukin 8Interleukin-8 is a chemokine produced by macrophages and other cell types such as epithelial cells. It is also synthesized by endothelial cells, which store IL-8 in their storage vesicles, the Weibel-Palade bodies...
: Many cancers have been found to produce and express IL-8. Binding of IL-8 to CXCR1 and CXCR2 receptors has been associated with tumorTumorA tumor or tumour is commonly used as a synonym for a neoplasm that appears enlarged in size. Tumor is not synonymous with cancer...
establishment. - SDF-1: Other cancers express high levels of SDF-1, which stimulates tumor growth and disrupts normal immune cell trafficking.
Inflammation
Inflammation
Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...
is one of the first responses of the immune system to infection or irritation. The response is stimulated by chemical factors released by injured cells. These chemical factors induce all associated inflammatory symptoms by sensitizing pain receptors, causing vasodilation of the blood vessels at the scene, and attracting phagocytes.
Neutrophils are the first to the scene, triggering other parts of the immune system by releasing factors to summon other leukocytes and lymphocytes. Other innate leukocytes include natural killer cells, mast cells, eosinophils, basophils, macrophages, and dendritic cells. These cells function in concert by identifying and eliminating pathogens that might cause infection.
As first responders, the innate immune cells cannot afford to be specific, and must respond to foreign substances in a generic way. Neutrophils, for example, contain toxic substances in their granules that kill or hinder the expansion of pathogens. The cells attack pathogens by releasing strong oxidizing agents including hydrogen peroxide
Hydrogen peroxide
Hydrogen peroxide is the simplest peroxide and an oxidizer. Hydrogen peroxide is a clear liquid, slightly more viscous than water. In dilute solution, it appears colorless. With its oxidizing properties, hydrogen peroxide is often used as a bleach or cleaning agent...
, free oxygen radicals, and hypochlorite
Hypochlorite
The hypochlorite ion, also known as chlorate anion is ClO−. A hypochlorite compound is a chemical compound containing this group, with chlorine in oxidation state +1.Hypochlorites are the salts of hypochlorous acid...
. Although the attack is effective against bacteria and fungi, the response can inadvertently inflict severe damage to the surrounding host tissue. The misregulation of innate immune cells plays a key role in promulgating inflammatory conditions.
Chemorepulsion is currently being explored as a practicable therapy for the prevention or resolution of unwanted inflammatory responses. A chemorepellent functions by conveying chemical signals to immune cells that instruct them to leave or stay away from a targeted area or tissue in order to restore the tissue to a normal state.
Graft rejections
The objective of using chemorepulsion therapy in transplantOrgan transplant
Organ transplantation is the moving of an organ from one body to another or from a donor site on the patient's own body, for the purpose of replacing the recipient's damaged or absent organ. The emerging field of regenerative medicine is allowing scientists and engineers to create organs to be...
ation medicine is to procure sustainable, site-specific unresponsiveness for the prevention of graft rejection. Current therapies achieve rejection control by indiscriminately suppressing the immune response. In this approach, any benefits achieved by immunosuppression
Immunosuppression
Immunosuppression involves an act that reduces the activation or efficacy of the immune system. Some portions of the immune system itself have immuno-suppressive effects on other parts of the immune system, and immunosuppression may occur as an adverse reaction to treatment of other...
are overcome by increasing the patient's risk of deadly, opportunistic infections. If attainable, constitutive expression of chemorepellents by the donor tissue would create an inducible immune-privileged site for the allograft, and would be an effective alternative treatment for graft rejection prevention.
Mechanism
Chemorepulsion is enabled by the same gradient-sensing capability that governs chemotaxisChemotaxis
Chemotaxis is the phenomenon in which somatic cells, bacteria, and other single-cell or multicellular organisms direct their movements according to certain chemicals in their environment. This is important for bacteria to find food by swimming towards the highest concentration of food molecules,...
. The gradient signal of the chemokinetic agent is received through specific receptors on the cell surface and is transduced through intracellular machinery to generate the directional response. The cell moves up a gradient
Gradient
In vector calculus, the gradient of a scalar field is a vector field that points in the direction of the greatest rate of increase of the scalar field, and whose magnitude is the greatest rate of change....
of a chemoattractant or down a gradient of a chemorepellent. In addition to axon
Axon
An axon is a long, slender projection of a nerve cell, or neuron, that conducts electrical impulses away from the neuron's cell body or soma....
growth cones, the model organism Dictyostelium discoideum has been instrumental in determining the mechanisms that mediate chemorepulsion and immunorepulsion. The mechanisms of gradient-sensing and cell polarization
Polarization
Polarization is a property of certain types of waves that describes the orientation of their oscillations. Electromagnetic waves, such as light, and gravitational waves exhibit polarization; acoustic waves in a gas or liquid do not have polarization because the direction of vibration and...
in D.discoideum are remarkably conserved in human neutrophils.
Bidirectional decisions
Leukocytes can exhibit active chemorepulsion away from a factor that is normally considered to stimulate chemoattraction depending on the context. For example, lymphocytes can migrate away from a high concentration of the chemokineChemokine
Chemokines are a family of small cytokines, or proteins secreted by cells. Their name is derived from their ability to induce directed chemotaxis in nearby responsive cells; they are chemotactic cytokines...
SDF-1 rather than be attracted by lower concentrations of the same factor. Similar results have been reported for human neutrophils to the chemokine IL-8
Interleukin 8
Interleukin-8 is a chemokine produced by macrophages and other cell types such as epithelial cells. It is also synthesized by endothelial cells, which store IL-8 in their storage vesicles, the Weibel-Palade bodies...
.
- • The directional decision to move towards or away from a chemokine appears to be determined by:
- • Differential receptorReceptor (biochemistry)In biochemistry, a receptor is a molecule found on the surface of a cell, which receives specific chemical signals from neighbouring cells or the wider environment within an organism...
occupancy - • Intracellular kinaseKinaseIn chemistry and biochemistry, a kinase is a type of enzyme that transfers phosphate groups from high-energy donor molecules, such as ATP, to specific substrates, a process referred to as phosphorylation. Kinases are part of the larger family of phosphotransferases...
activation - • Cyclic nucleotideNucleotideNucleotides are molecules that, when joined together, make up the structural units of RNA and DNA. In addition, nucleotides participate in cellular signaling , and are incorporated into important cofactors of enzymatic reactions...
concentrations
Signaling pathways
| Abbreviations Legend |
|---|
| • PI3K Phosphoinositide 3-kinase |
| • PLC Phospholipase C |
| • cAMP Cyclic adenosine monophosphate, a chemoattractant |
| • 8CPT-cAMP 8-para-chlorphenylthio, a chemorepellent |
| • IP-3 Inositol trisphosphate |
| • Pt dIns(3,4,5)P3 Phosphatidylinositol (3,4,5)-triphosphate |
| • SDF-1 Stromal cell-derived factor 1 |
In both D. discoidium and human neutrophils, there is a reversal of polarity that occurs when converting from a chemoattraction to a chemorepulsion response. Evidenced chemotaxis models have been observed using cAMP
Cyclic adenosine monophosphate
Cyclic adenosine monophosphate is a second messenger important in many biological processes...
analogs. During cAMP-mediated chemoattraction, the chemoattractant cAMP acti vates PI3K at the leading edge
Leading edge
The leading edge is the part of the wing that first contacts the air; alternatively it is the foremost edge of an airfoil section. The first is an aerodynamic definition, the second a structural one....
along with the localized activation of the small GTPases Rac
RAC
-Companies:* Rent-A-Center, an American public furniture and electronics rent to own company* Royal Automobile Club, a private club in Pall Mall, London* RAC plc, a breakdown company in the United Kingdom...
and Cdc42
CDC42
Cell division control protein 42 homolog also known as CDC42 is a protein involved in regulation of the cell cycle. In humans, CDC42 is encoded by the CDC42 gene.- Function :...
. This in turn activates PLC
Phospholipase C
Phosphoinositide phospholipase C is a family of eukaryotic intracellular enzymes that play an important role in signal transduction processes. In general, this enzyme is denoted as Phospholipase C, although three other families of phospholipase C enzymes have been identified in bacteria and in...
which leads to the generation of IP-3, which results in a loss of PtdIns(4,5)P2 at the leading edge. The chemorepellent 8CPT-cAMP inhibits PLC activity and thereby increases Ptds(3,4,5)P3 accumulation and activation of PTEN
PTEN (gene)
Phosphatase and tensin homolog is a protein that, in humans, is encoded by the PTEN gene. Mutations of this gene are a step in the development of many cancers....
. In this manner, the chemorepellant reverses the polarity
Chemical polarity
In chemistry, polarity refers to a separation of electric charge leading to a molecule or its chemical groups having an electric dipole or multipole moment. Polar molecules interact through dipole–dipole intermolecular forces and hydrogen bonds. Molecular polarity is dependent on the difference in...
of the PtdIns(3,4,5)P3 gradient and induces chemorepulsion. Recent evidence also implicates a role for PI5K and Rho
Rho
Rho is the 17th letter of the Greek alphabet. In the system of Greek numerals, it has a value of 100. It is derived from Semitic resh "head"...
signaling during directional decision making and migration.
Inhibitors
Useful inhibitors have been investigated in T cells. For example, T cell chemoattration to SDF-1 is inhibited by the tyrosineTyrosine
Tyrosine or 4-hydroxyphenylalanine, is one of the 22 amino acids that are used by cells to synthesize proteins. Its codons are UAC and UAU. It is a non-essential amino acid with a polar side group...
kinase
Kinase
In chemistry and biochemistry, a kinase is a type of enzyme that transfers phosphate groups from high-energy donor molecules, such as ATP, to specific substrates, a process referred to as phosphorylation. Kinases are part of the larger family of phosphotransferases...
inhibitors, genistein and herbimycin.