Page last updated: 2024-10-24

negative regulation of leukocyte proliferation

Definition

Target type: biologicalprocess

Any process that stops, prevents, or reduces the frequency, rate or extent of leukocyte proliferation. [GOC:add, GOC:mah]

Negative regulation of leukocyte proliferation is a complex process involving various cellular and molecular mechanisms that restrain the growth and division of leukocytes, ultimately preventing uncontrolled immune responses and maintaining immune homeostasis. This process is crucial for preventing excessive inflammation, autoimmune disorders, and the development of leukemia.

Key mechanisms involved in negative regulation of leukocyte proliferation include:

1. **Cytokine signaling:**
* **TGF-beta:** A potent immunosuppressive cytokine that inhibits the proliferation of various leukocyte populations, including T cells, B cells, and NK cells. It achieves this by activating signaling pathways that induce cell cycle arrest and promote apoptosis.
* **IL-10:** Another immunosuppressive cytokine that primarily targets activated T cells, reducing their proliferation and cytokine production. IL-10 exerts its effect by inhibiting the expression of pro-inflammatory cytokines and promoting the differentiation of regulatory T cells.
* **IL-12:** While primarily known for its pro-inflammatory role, IL-12 also contributes to negative regulation by promoting the differentiation of regulatory T cells, which suppress the proliferation of other T cells.

2. **Apoptosis:** Programmed cell death is a critical mechanism for eliminating activated leukocytes after an immune response. It is triggered by various factors, including cytokine withdrawal, DNA damage, and activation of death receptors.

3. **Immune checkpoint molecules:** These proteins expressed on immune cells act as brakes to prevent excessive activation.
* **CTLA-4:** A receptor expressed on T cells that binds to the same ligands as CD28, a costimulatory molecule. By competing with CD28, CTLA-4 inhibits T cell activation and proliferation.
* **PD-1:** Another inhibitory receptor expressed on T cells, which interacts with PD-L1 and PD-L2 ligands on antigen-presenting cells. PD-1 signaling suppresses T cell activation and proliferation.

4. **Regulatory T cells (Tregs):** These specialized T cell subsets actively suppress the proliferation of other immune cells, maintaining immune tolerance and preventing autoimmunity. Tregs accomplish this through various mechanisms, including the production of immunosuppressive cytokines like IL-10 and TGF-beta, and the expression of inhibitory molecules like CTLA-4.

5. **Other mechanisms:**
* **Hypoxia:** Low oxygen levels in the tumor microenvironment can suppress leukocyte proliferation and activation, contributing to immune evasion by cancer cells.
* **Metabolic reprogramming:** Leukocytes require specific metabolic pathways for proliferation and activation. Inhibiting these pathways can effectively reduce leukocyte growth.

Overall, negative regulation of leukocyte proliferation is a complex and multi-faceted process that involves a delicate balance of positive and negative signals. Disruptions in this regulatory network can lead to various pathological conditions, highlighting the crucial role of these mechanisms in maintaining immune homeostasis.'
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Proteins (1)

ProteinDefinitionTaxonomy
Glutathione S-transferase PA glutathione S-transferase P that is encoded in the genome of human. [PRO:DNx, UniProtKB:P09211]Homo sapiens (human)

Compounds (10)

CompoundDefinitionClassesRoles
ethacrynic acidetacrynic acid : An aromatic ether that is phenoxyacetic acid in which the phenyl ring is substituted by chlorines at positions 2 and 3, and by a 2-methylidenebutanoyl group at position 4. It is a loop diuretic used to treat high blood pressure resulting from diseases such as congestive heart failure, liver failure, and kidney failure. It is also a glutathione S-transferase (EC 2.5.1.18) inhibitor.

Ethacrynic Acid: A compound that inhibits symport of sodium, potassium, and chloride primarily in the ascending limb of Henle, but also in the proximal and distal tubules. This pharmacological action results in excretion of these ions, increased urinary output, and reduction in extracellular fluid. This compound has been classified as a loop or high ceiling diuretic.
aromatic ether;
aromatic ketone;
dichlorobenzene;
monocarboxylic acid
EC 2.5.1.18 (glutathione transferase) inhibitor;
ion transport inhibitor;
loop diuretic
d-alpha tocopherol(R,R,R)-alpha-tocopherol : An alpha-tocopherol that has R,R,R configuration. The naturally occurring stereoisomer of alpha-tocopherol, it is found particularly in sunflower and olive oils.

tocopherol : A collective name for a group of closely related lipids that contain a chroman-6-ol nucleus substituted at position 2 by a methyl group and by a saturated hydrocarbon chain consisting of three isoprenoid units. They are designated as alpha-, beta-, gamma-, and delta-tocopherol depending on the number and position of additional methyl substituents on the aromatic ring. Tocopherols occur in vegetable oils and vegetable oil products, almost exclusively with R,R,R configuration. Tocotrienols differ from tocopherols only in having three double bonds in the hydrocarbon chain.

vitamin E : Any member of a group of fat-soluble chromanols that exhibit biological activity against vitamin E deficiency. The vitamers in this class consists of a chroman-6-ol core which is substituted at position 2 by a methyl group and (also at position 2) either a saturated or a triply-unsaturated hydrocarbon chain consisting of three isoprenoid units. The major function of vitamin E is to act as a natural antioxidant by scavenging free radicals and molecular oxygen.

Vitamin E: A generic descriptor for all TOCOPHEROLS and TOCOTRIENOLS that exhibit ALPHA-TOCOPHEROL activity. By virtue of the phenolic hydrogen on the 2H-1-benzopyran-6-ol nucleus, these compounds exhibit varying degree of antioxidant activity, depending on the site and number of methyl groups and the type of ISOPRENOIDS.
alpha-tocopherolalgal metabolite;
antiatherogenic agent;
anticoagulant;
antioxidant;
antiviral agent;
EC 2.7.11.13 (protein kinase C) inhibitor;
immunomodulator;
micronutrient;
nutraceutical;
plant metabolite
hexylglutathioneS-hexylglutathione : An S-substituted glutathione that is glutathione in which the hydrogen of the thiol has been replaced by a hexyl group (PDB entry: 1PN9).S-substituted glutathione
5-chloromethylfluorescein diacetateacetate esterfluorochrome
malagashaninemalagashanine: from Strychnos sp.; structure given in first source
curcumincurcumin : A beta-diketone that is methane in which two of the hydrogens are substituted by feruloyl groups. A natural dyestuff found in the root of Curcuma longa.

Curcumin: A yellow-orange dye obtained from tumeric, the powdered root of CURCUMA longa. It is used in the preparation of curcuma paper and the detection of boron. Curcumin appears to possess a spectrum of pharmacological properties, due primarily to its inhibitory effects on metabolic enzymes.
aromatic ether;
beta-diketone;
diarylheptanoid;
enone;
polyphenol
anti-inflammatory agent;
antifungal agent;
antineoplastic agent;
biological pigment;
contraceptive drug;
dye;
EC 1.1.1.205 (IMP dehydrogenase) inhibitor;
EC 1.1.1.21 (aldehyde reductase) inhibitor;
EC 1.1.1.25 (shikimate dehydrogenase) inhibitor;
EC 1.6.5.2 [NAD(P)H dehydrogenase (quinone)] inhibitor;
EC 1.8.1.9 (thioredoxin reductase) inhibitor;
EC 2.7.10.2 (non-specific protein-tyrosine kinase) inhibitor;
EC 3.5.1.98 (histone deacetylase) inhibitor;
flavouring agent;
food colouring;
geroprotector;
hepatoprotective agent;
immunomodulator;
iron chelator;
ligand;
lipoxygenase inhibitor;
metabolite;
neuroprotective agent;
nutraceutical;
radical scavenger
ellagic acidcatechols;
cyclic ketone;
lactone;
organic heterotetracyclic compound;
polyphenol
antioxidant;
EC 1.14.18.1 (tyrosinase) inhibitor;
EC 2.3.1.5 (arylamine N-acetyltransferase) inhibitor;
EC 2.4.1.1 (glycogen phosphorylase) inhibitor;
EC 2.5.1.18 (glutathione transferase) inhibitor;
EC 2.7.1.127 (inositol-trisphosphate 3-kinase) inhibitor;
EC 2.7.1.151 (inositol-polyphosphate multikinase) inhibitor;
EC 2.7.4.6 (nucleoside-diphosphate kinase) inhibitor;
EC 2.7.7.7 (DNA-directed DNA polymerase) inhibitor;
EC 5.99.1.2 (DNA topoisomerase) inhibitor;
EC 5.99.1.3 [DNA topoisomerase (ATP-hydrolysing)] inhibitor;
food additive;
fungal metabolite;
geroprotector;
plant metabolite;
skin lightening agent
2-crotonyloxymethyl-2-cyclohexenone2-crotonyloxymethyl-2-cyclohexenone: structure given in first source
6-(7-nitro-2,1,3-benzoxadiazol-4-ylthio)hexanol6-(7-nitro-2,1,3-benzoxadiazol-4-ylthio)hexanol: a specific glutathione S-transferase inhibitor; structure in first source
flavellagic acidflavellagic acid: RN given refers to parent cpd; structure