Cytokines are low molecular weight proteins or peptides that are important signaling molecules that regulate immunity and inflammation. They act as intercellular messengers to regulate the intensity and duration of immune responses by binding to receptors on target cells. There are four main structural families of cytokines - hematopoietin receptor family, interferon receptor family, TNF receptor family, and chemokine receptor family. Cytokines can act through autocrine, paracrine, or endocrine signaling and activate signaling pathways like JAK-STAT. An imbalance in the levels of cytokines produced by TH1 and TH2 cells can lead to different disease outcomes. Cytokine-related diseases include septic shock, toxic shock syndrome, and some cancers and infections.

1. CYTOKINE
S
BY
POOJA SEVAK
JRF
DEPT. OF BIOTECH
UNIVERSITY OF MUMBAI

2. What is Cytokine ???
• Low molecular weight proteins (30 KDa)
• Bind receptors, alter gene expression
• Very low Kd receptors (10-10-10-12 M)
• Cytokines regulate immune responses
•Decide intensity and duration of immune response

3. How cytokine act ????

4. cytokine
action

5. Cytokine

6. Cytokine Action Can Be….
• Autocrine
• Paracrine
• Endocrine

7. Fig:- Cytokine Action

8. Cytokine activity
•Pleiotropy
•Redundancy
•Synergy
•Antagonism
•Cascade induction

10. Cytokine Assay
-The biological activities of cytokines can be measured by a
variety of bioassays which may employ factor-dependent
cell lines, or antibodies (ELISA)
-RT-PCR quantitation of cytokines detects the presence of
mRNA encoding specific cytokines

11. Cytokine Belong to Four Structural Families
• Hematopoietin Receptor Family (Class I)
•Interferon Receptor Family (Class II)
•TNF Receptor Family
•Chemokine Receptor Family

12. Interleukin-2 Interleukin-4

13. Cytokine Receptors

14. Type of Cytokine Receptor
• Immunolglobulin superfamily receptors
• Class I cytokine receptor family (also known as
hematopoietin receptors family)
• Class II cytokine receptor family (also known as
Interferon receptors family)
• TNF receptor superfamily
• Chemokine receptors

15. 1. Immunolglobulin superfamily receptors
Ligands- IL

16. 2. Class I cytokine receptor family (also
known as hematopoietin receptors family)

17. Three subfamilies of the class I
cytokine receptor family
(hematopoietin)

19. • GM-CSF has antagonistic effect
• GM-CSF is inhibited by IL-3
• Low affinity
• Low affinity subunit associated with beta subunit
• Induce eosinophil proliferation and basophil
degranulation

23. • Alpha chain responsible for binding to cytokine, other
subunit for signal transduction
• Induce synthesis of acute phase proteins by liver
hepatocytes
• Differentiation of myeloid leukemia cell into
macrophage

25. • Common gamma subunit
• Alpha for cytokine binding and beta and gamma for signal
transduction
• X- linked severe combined immunodeficiency due to defect
in
gamma chain
• Most widely studied cytokine receptor as responsible for T
cell activation
• IL-2 receptor is present in 3 forms: low, medium, and high
affinity
• The low affinity (monomeric, IL-2Ra), medium affinity
(dimeric, IL-2Ra), and high affinity (trimeric, IL-2Rag)

26. • Gamma subunit is constitutively expressed
• Alpha and beta expressed after activation by
antigen
• Activated CD4+ and CD8+ cell expresses high
affinity IL-2

27. 3. Class II cytokine receptor family (also
known as Interferon receptors family)

28. 4. TNF receptor superfamily

29. 5. Chemokine receptors

30. Activation of Signal Transduction Pathway by
Cytokine
• Mostly involved class I and class II receptors
• Activation of protein tyrosine kinase
• INF-у is mostly studies example of signal transduction

31. • A number of cytokine receptors signal via the JAK/STAT pathway.
These include the receptors for IL-2, IL-3, IL-4, IL-6, IL-10, IL-12 and
IFN-g.
• Cytokine receptor subunits are associated with JAK kinases.
1.- Binding of cytokine causes dimerization of receptors and
activation of JAK kinases.
2.- Activated JAK kinases phosphorylate receptor sites and create
docking sites for STAT molecules.
3. - After binding to the receptor (a chain), STATs are phosphorylated.
4. - They then dissociate from the receptor, dimerize and translocate
to the nucleus, where they mediate transcription of target genes.

32. Fig:- Signal Transduction Pathway

33. Other pathways
may also be
involved in
cytokine signaling
Fig:- Signal Transduction Pathway

34. What decide the Specificity of
Cytokine Activity ??????
• Binding of cytokine to
its receptor
• Particular JAK-STAT
combination
• STAT homo and
heterodimer
• Cell type

35. Cytokine Antagonists
– Inhibit the biological activity of cytokines
•Bind to the cytokine receptor
•Bind to the cytokine
– Be found in the bloodstream and extracellular fluid
– Some virus can produce cytokine-binding protein
or cytokine mimics
– Determine the intensity of the response
– IL-1Ra and sIL-2R (Biomarker for various diseases)

36. Virus mimic some cytokine

37. Fig:- Cytokine antagonist

38. Cytokine by TH1 and TH2 cells
• TH1 induces cell mediated functions and opsonization
promoting IgG antibody
• TH1 involve excessive inflammation and tissue injury
• TH2 eosinophil activation, IgM and IgE production and
also noncomplement activating IgG isotype
• Support allergic reaction

39. Fig:- Cross regulation of TH1 and TH2 cells

40. Cytokine cross-regulation
•
• IFN-g (Th-1) inhibits proliferation of Th-2
• IL-4 and IL-10 (Th-2) inhibits proliferation of Th-1 by
decreasing IL-12 production
• INF-g (Th-1) promotes IgG2a production and
decreases IgE by B cells
• IL-4 (Th-2) promotes production of IgE and IgG1 by
B-cells and decreases IgG2a.
• Role of T-Bet and GATA-3

41. Fig:- Regulation of TH1 and TH2 cells by
T-Bet and GATA-3

42. Disease Outcome Determination by
TH1/TH2 Balance
Fig:- TH1 or TH2 activity toward disease

43. Cytokine –Related Diseases
• Bacterial septic shock
 Cytokine overproduction
 Bacterial cell-wall endotoxins marcophage to overproduce
IL-1 and TNF-alpha

44. • Bacterial toxic shock and similar diseases
 Bacteria produce toxins that act as superantigens
 The large number of T cells activated which result in
excessive production of cytokines
 Antigen bind to V-beta domain of TCR
 Enterotoxin, Exfoliating toxins, toxic shock syndrome
toxin from S. aureus

45. • Lymphoid and myeloid cancers
 Cytokines and their receptors abnormally produced
 IL-6 overproduction lead to plasmacytosis which
result in cancer

46. Chagas’s Disease
• Caused by Trypanosoma cruzi
• Decrease inalpha subunit of IL-2 receptor

47. Therapeutic Use of Cytokines
Used in treatment of
• Inflammation
• Cancer therapy
• During organ transplant
• Allergy

48. Fig:- Suppression of TH cell proliferation and TC cell
activation

49. Fig:- Destruction of activated TH cell

50. Problems Associated with
Cytokine therapy
• To achieve local concentration
• Short half life of cytokine
• Unpredicted and undesirble side effects

51. Cytokines play essential role in hematopoiesis

52. Thank You