Cytokines and the Control of Hematopoiesis

Hematopoietic growth factor cytokines are specific glycoproteins that regulate and control hematopoiesis.

Functions of hematopoietic growth factor cytokines:- 

• Promote cell survival (suppress apoptosis). 
• Promote proliferation. 
• Control & regulate the processes of differentiation.

Characteristics of Growth Factors:-

• Produced by stromal cells in B.M. (except: Epo).
• Generally, more than one GP needed to control hematopoietic.
• React with specific membrane receptors.
• Affect hematopoiesis directly or indirectly.
• Act synergistically with each other.
• The majority have multiple biologic activities (not lineage specific).
• GP = Glycoprotein.

Early-Acting (Multilineage) GFs

• Act on multipotential precursor cells. 
• SCF, FL, IL-3, GM-CSF, IL-6 & IL-11 . 

SCF:

• SCF = Stem Cell Factor = Steel Factor “SF” = kit ligand “KL” = Mast Cell Growth Factor “MCGF” . 
• Proliferation & differentiation of CFU-GEMM, CFU-GM, CFU-Mk, BFU-E. 
• Also promotes the survival, proliferation & differentiation of mast cell precursors.
• Plays role in normal melanocyte development & gametogenesis.

 Flt3 ligand (FL):

• Increases recruitment of primitive HSC into the cell cycle & inhibits apoptosis.
• Flt3 ligand has little effect on unilieage BFU-E/CFU-E, CFU-mast cell or CFU-Eo but it is a potent stimulator of granulocytic, B cell, & dendritic cell proliferation & differentiation.
• HSC = Hematopoietic Stem Cell.

 IL-3: 

• Affects multilineage progenitor cells & early commited progenitors like BFU-E.
• Also has indirect actions & can can induce the expression of other cytokines.

GM-CSF: 

• Affects CFU-GEMM, BFU-E, CFU-Mk, CFU-GM, & CFU-Eo. 
• GM-CSF: it is a major promoter of granulocyte & monocyte differentiation, but lacks a significant effect on basophil production. 
• GM-CSF also activates the functional activities of most nature phagocytes, including neutrophils, macrophages & eosinophils. 

IL-6 & IL-11:

• They are pleiotropic cytokines with overlapping growth stimulatory effects on myeloid & lymphoid cells as well as on primitive multilineage cells. 
• Significant effects on megakaryopoiesis & platelet production. 
• Both also mediate the acute phase response of hepatocytes. Also they are major pyrogens in vivo. 

IL-11:

• Shortens the duration of G0 of primitive hematopoietic progenitor cell & hastens hematopoietic recovery after treatment with cytotoxic agents or B.M. transplantation.

Later-Acting (Lineage-Restricted) GFs

• G-CSF : granulocytes.  
• M-CSF : monocytes. (Also regulates the genesis of osteoclasts).  
• EPO : RBCs.  
• TPO : megakaryocytes & platelets.  
• IL-5 : eosinophils. (Also stimulates lymphocyte development).  
• The other interleukins important in lymphopoiesis (ILs-2, -4, -7, -10, -12, -13, -14, -15).

Erythropoietin (EPO):

• The only cytokine to function as true hormone. 
• Embryonic life: produced largely by liver. 
• Adult life: largely produced by kidney (~ 90%), & by liver (to a lesser extent; ~ 10%). 
• Production is regulated by the oxygen needs; induced by hypoxia. 
• Stimulates growth, survival, & differentiation of erythroid progenitor cells (major effect on CFU-E); & stimulates proliferation & RNA synthesis in more well-differentiated maturing cells. 
• Reticulocytes & mature erythrocytes do not have receptors for EPO; so they are not affected by EPO.

Thrombopoietin (TPO):

• TPO = mpl-ligand = megakaryocyte growth & development factor (MGDF). Megakaryocyte & platelet production.
• In vitro, make/primes mature platelets to respond to aggregation-inducing stimuli & increases the platelet release reaction.
• Act with a variety of other GFs (SCF, IL-3, FL) to stimulate the growth of primitive progenitor cell.

Indirect-Acting Growth Factors

• Some cytokines that regulate hematopoiesis do so indirectly. 
• Example: IL-1 . 
• IL-1: has no colony-stimulating activity itself, but it induces neutrophilic leukocytosis, resulting from the release of other direct-acting cytokines by accessory cells.