immunolec2

Tyrosine kinase (M-CSF, SCF, Flt-3L)

- contain a 4 helix bundle structure

- receptors are tyrosine kinases

- Stem Cell Factor (SCF), receptor = c-kit (C117)

- fms-like tyrosine kinase 3 ligand (FLt-3L), receptor = Flt-3R (CD135)

      - SCF and Flt-3L act very early on in haematopoiesis and are pleiotropic

- M-CSF, R = c-fms (CD115)

      - specific for the macrophage lineage

Colony stimulating factors

- subclass of cytokine superfamily

- protein factors able to stimulate the production of one or more colony type in semi-solid cultures of bone marrow or other haematopoietic tissue

- IL-3, IL-5, GM-CSF, Epo, Tpo, G-CSF, IL-6, LIF, OSM, M-CSF, SCF, FLT-3L

- produced by activated macrophages/T-cells and other cell types

- bind specific receptors

  -> some have receptor subunits in common

  -> stimulate signal transduction leading to transcription factor activation enhancing proliferation, viability, differentiation

Cytokines

Small secreted glycoproteins which mediate and regulate immunity, inflammation and haematopoiesis, which bind to specific receptors on target cells.

Lymphokines - mediators of immune responses, released by sensitized lymphocytes on contact with antigen

Chemokines - chemotactic cytokines

Interleukins - affect primary cells and are derived from macrophages and T cells that have been stimulated by antigens or mitogens

Growth factors - stimulate growth

Thrombopoietin (Tpo)

- produced by the liver and kidney, as well as striated muscle and stromal cells in the bone marrow

- production in the liver augmented by IL-6

- regulates differentiation of megakaryocytes and platelets

  -> Tpo receptor KO studies show its effects on haemopoiesis are more widespread

- negative feedback different from most hormones

  -> the effector regulates the hormone directly

  -> Tpo binds to surface of platelets, thereby reducing megakaryocyte exposure to Tpo

Erythropoietin (Epo)

- stimulates the proliferation, viability and differentiation of erythroid progenitors

- produced mainly by kidneys

- acts on bone marrow to producing more mature RBCs

- Epo used clinically to treat anaemia and in renal failure

- also used by athletes, can cause death (high haematocrits)

   -> can be detected in urine up to 3 days after doping

   -> changes in transferrin:ferritin ratios can be detected up to 3 weeks after         doping

Beta-C family (IL3, IL5, GM-CSF)

- all 3 have specific alpha-receptors and a common beta-receptor subunit

- beta-subunit transmits signal, so signalling pathways initiated are very similar

- the beta-C receptor chain activates JAK2 kinase leading to STAT activation, many pathways activated, raf-MAPK pathway, PI3-K pathway

- results in differentiation, proliferation and viability signals

- IL-3: multi-lineage (pleiotropic)

- IL-5: eosinophil-lineage

- GM-CSF: granulocyte/macrophage lineage