This document provides an overview of cytokines, including their definition, properties, nomenclature, functions, receptor families, signaling pathways, roles in various diseases, and clinical applications. Specifically, it discusses cytokines' roles in communication between immune cells and other body cells, their pleiotropic and redundant effects, classes of primary and secondary cytokines, T cell subsets defined by their cytokine profiles, the JAK-STAT and NF-kB signaling pathways, the eight families of cytokine receptors, examples of important cytokines such as IL-2, IL-4, TNF, and IFN-γ, diseases associated with different cytokine profiles like Th1/Th17 cytokines in psoriasis and Th2 cytokines in atopic dermatitis, and

1. Dr.Amy Mary Sebastian

2. Topic overview
• Cytokines: definition & properties
• Nomenclature
• Primary & secondary CKs
• T cell subsets
• Signal transduction pathways- JAK-STAT, NF-kB
pathway
• Classification of CKs – 8 families based on receptors
• CK- Applied aspect
• Biologicals targeting CKs
• Adverse reactions to CKs

3. • Soluble polypeptide mediators – pivotal role –
communication b/n cells of hematopoietic system
& other cells in the body
• Non immunoglobulin proteins(8-30 kd)
• Released transiently in tissue micro environment
as emergency molecules

4. • Term cytokine coined by Cohen in 1975
• Functions:

5. General features of CKs
Pleiotropism
Multiple biologic activities
Redundancy
Overlapping biologic effects
• Endogenou
s pyrogen
• Lymphocyt
e activating
factor
• Leucocytic
endogenou
s mediator
IIL 1

6. •Cytokines were named according to:
•Cells of origin: Lymphocytes-Lymphokine
Monocytes- Monokine
•Function: GM-CSF- growth factor
Chemokines- chemotaxis
•Targets: Interleukins- leucocytes ,but also acts
on other cells
•All newly discovered CKs are called ILs- 1 to 38
according to order of discovery

7. Primary & Secondary CKs
Primary CKs –initiate all the
events for leucocyte
infiltration by themselves
Secondary CKs- Production
after stimulation by primary
CKs, Restricted spectrum of
activity
IL 1,TNF
IL-2 IL-15
IL-4
IL-13

8. Additional proposed subsets
Tfh(Follicular helper T cells)-
helps B cells in germinal
centres
Th9 cells-IL 9
-antiparasite immunity
Th22 cells- IL 22
-Skin inflammation

9. Signal transduction pathways: NF-kB
IL-17,18 Also by bac LPS, Viruses, UV, Oxidants
IkB Kinase complex (IKK), IKK⍺, IKK

10. JAK-STAT Pathway-
Janus kinase, Signal transducer & activation
of transcription
Signaling by Class I & II CKs
4 Tyrosine kinases: Jak 1
Jak 2
Jak 3
Tyk 2
SH2 domain- Src homology 2
domain
Docking proteins

11. CK families (according to receptors)
1.Class I- largest
Haematopoietin
Receptor
Family
2.Class II
IFN/IL 10
Receptor
family
3)TNF 4)IL-1 5)IL-17 6)TGF-β 8)PDGF
7)Chemokines

12. 1.Class I-Hematopoietin receptor family
• Membrane bound glycoproteins
• Jak-STAT pathway
• Multiple chain receptors-
CK specific ⍺ chain subunit
one or more shared subunits
• 5 shared receptor subunits:
𝜸c βc(IL-2,15) GP-130
IL-3Rβ
IL-3,5
GM-CSF
IL-12Rβ2
IL-12,23
IL-6,11,27
Leukemia inhibitory
factor

13. Receptors sharing common 𝛾 chain- 𝛾c
TSLP IL-21 IL-13
(CD-25)
Lymphoid cells Lymphoid cells
Keratinocytes
Fibroblasts
Dendritic cells,monocytes- LPS
UV induced

14. • Reigns autoreactive T
cells
• Inhibits proliferation of
memory CD8 T cells
• Prolonged stimulation-
FasL & activation
induced cell death
• + Effector function of
antigen specific T cells
• Promotes proliferation of
memory CD8 T cells, NK
cells
• IL 15 inhibits activation
induced cell death
i) IL-2 & IL 15

15. ii)IL-4 & IL-13-Th2
cells
(CD 124)
T cells ,NK cells
Specific
Keratinocytes,EC
Non specific
IL-4 –Growth &
differenciation of Th2 cells

16. iii)IL-7 & Thymic stromal lyphopoietin(TSLP)
Lymphocytes in skin
Regulated expression
DC- IFN 𝜸- KC- IL 7- DC
Immature lymphocytes in BM & Thymus
Lymphocytes
GF for B & T cells
Prime DC s
In some allergic Ds
Th2 cells (TGF 𝜷)
Mast cells (IL 10/SCF)
Allergic
Responce

17. iv)IL-3, IL-5 & GM-CSF
(CD-131)
Produced by: CD4 cells T cells,KC,EC Th2,Mast cells
Mutilineage CSF GF for myeloid Pool of eosinophil
(Myeloid cells) DC to mature DC precursors in BM
Eotaxin

18. • IL-6- Highly pleiotropic,from KC,EC,fibroblasts
• B cell stimulatory factor- Ig secretion
• Plasmacytoma GF- mitogenic for plasmacytoma
• Hepatocyte stimulatory factor
- synthesize acute phase proteins
• IL 11-inhibits production of inflam CKs-Psoriasis
v) gp 130- IL-6, IL-11, IL-27,
Leukemia inhibitory factor, Oncostatin M

19. Pivotal CKs regulating Th1 & Th17 response
Contact
allergens
UV
exposure
Anti tumor immunity Memory T cells Early T cell Treg cells +
Intracellular bacteria Th17 subset response suppress Th17 cells

20. • 3 types of IFNs-Type 1- IFN⍺ (leucocyte IFN)
- IFNβ (Fibroblast IFN)
• (2 chain IFN⍺β receptor)
• Inhibits viral replication
• Some bacterial & protozoal immunity
• Type 2-IFN 𝛾-specific 2 chain receptor-
Stimulation of T cells, antiviral,antiproliferative
• Type 3-IFN𝜆1 / IL 28A
- IFN𝜆2/ IL 28B
• Antiviral, Receptor IL28R & IL 10R
2.Class II family- IFNs

21. 2.Class II family- IFNs & IL-10
Jak1 & Tyk2
STAT 1 & 3

22. 2.Class II family- IFNs & IL-10
• IL-10- antinflammatory CK
-produced by Th2 cells
-IL10R ⍺ & β
-decreases production of IL- 1, 6 & 12, Th1 CKs
-activates Th2 cells
-Keratinocytes are the major source-UV radiation
-Novel IL-10 related CKs-IL-19,20,22,24,26

23. 3.TNF receptor family
• TNF-⍺ -soluble form-resp for most actions-TACE
-Trans membrane protein form
• TNF-β (Lymphotoxin ⍺)
-homotrimer

24. 3.TNF receptor family
DD- Death domain
TRADD- TNF
Receptor asso DD
FADD-Fas
associated DD
DED-Death effector
domain
TRAF2 –TNF
receptor asso
factor 2

25. 4.IL-1 receptor family-IL-1⍺, 1β, 18 & 33
• IL-1- 31kDa
• IL-1⍺ biologically active, stored in keratinocytes
• IL-1β –must be cleaved by Caspase 1 in
inflammasome
- Egress of LCs from skin to draining LNs

26. 4.IL-1 receptor family-IL-1⍺, 1β, 18 & 33
IL-1R asso
kinases
TNF Receptor
asso Factor 6
IL-1ra

27. 4.IL-1 receptor family-IL-1⍺, 1β, 18 & 33
• IL-1R2 -68kDa receptor,regulatory function
-binds IL-1 but not IL-1ra
-after binding-cleaves into a 45kDa
molecule- sequesters IL-1
- also binds to IL1AcP-sequestering it
• IL-1R2 – upregulated by corticosteroids,IL-4
-Inflam CKs-IFN𝛾, IL-1
• IL-18 –proposed name IL-1𝛾
+ Th1 & NK cells

28. 5.IL-17 receptor family (IL-17 & 32)
• Th17 cells-produce IL-17A & IL-17F
• IL-17 mobilizes neutrophils
• TNF⍺,IL-1β,IL-8,IL-6 & G-CSF
• ICAM 1 by monocytes & fibroblasts
• Modulates CK production by keratinocytes-
Ps,AD,CD
• IL-32 : TNF⍺,IL-1β,IL-6
• Several autoimmune ds

29. • Misnomer- anti-proliferative
• Includes – prototypic TGFs- β 1 to β3
- BMP
- growth or differenciation factors
- activins
• Inactive precursor- prodomain cleaved- dimers of
mature domain
• TGF+ Type II receptor-Type I & II Cx- SMADs
6.TGF-𝛽 receptor family

30. • TGF β1 functions-
Treg cell & DC lineage formation
Pro fibrogenic- + Metalloproteinase formation
- TIMP
6.TGF-𝛽 receptor family

31. • CSF-1 isoform a
• EGF
• Hepatocyte GF isoform 1 preprotein
• PDGF C
• VEGF B
• VEGF C preprotein
6.PDGF family

32. • Psoriasis-
Th1 & Th17 inflam ds
• Shift from Th1 to Th2
improves psoriasis
• Over expression of type 1 CKs-IL-2 , IL-6, IL-8,
IL-12, IFN-𝛾, TNF ⍺
• IL-15-triggers production of IFN-𝛾, TNF ⍺,IL-17
• Over expression of IL8 -Neutrophil accumulation
• Th22 cells
Applied aspects

33. Applied aspects
Atopic dermatitis- Th2 phenotype
• TSLP(keratinocytes) through its interaction
with mast cells & DC- Th2 response
• TSLP, Th2 & Th22 lymphoid cells are
increased in atopic skin
• Th2 & Th22 – IL 31-itching & reduced filaggrin
expression

34. •
Applied aspects
• Bullous pemphigoid- Th2 CKs are important
• TNF⍺, IL-6,IL-8,IL-15,IL-21 levels correlate with
disease activity
• IL4 & 13 producing lymphocytes are increased in
peripheral blood
• Recently Th17 cells
• SLE-Ag-Ab Cx- stimulate TLRs 9 & 7-IFN⍺,TNF-⍺
• Increased IFN𝛾 ,IL-6 & IL-10

35. Applied aspects
“The mystery behind Koebner”
• Keratinocytes are rich in IL-1
• IL1ra also coexist
• Mechanical stress- releases large amounts of IL1
• Induces- E selectins,ICAM-1 & VCAM-1-
Chemokines
• Stimulates memory T cells & release of CKs
IL 1
IL1ra

36. Biologicals targeting CKs
• Anti-TNF⍺: Etanercept , Infliximab , Adalimumab
Certolizumab, Golimumab
• Anti-IL1:Anakinra, Rilonacept, Canakinumab
(r-IL-1Ra) (IL-1R+IL-1RacP) (anti IL-1β Ab)
• Anti-IL6:Tocilizumab, Siltuximab
•
• Th 17 CKs: Ustekinumab, Secukinumab,
Ixekizumab

37. •G-CSF-Induction of sweets syndrome, bullous PG
-Rarely thrombotic & necrotising panniculitis
-Exacerbation of leukocytoclastic vasculitis
•IFN⍺,IFN-𝛾,G-CSF- exacerbation of psoriasis
•IL-2-Pruritus,diffuse erythema,mucositis
Inj of iodinated contrast media within 2 wks,HS in
30% cases
Adverse reactions to cytokines

38. Adverse reactions to Anti-TNF⍺
• Psoriasis & psoriasiform
dermatitis(Adalimumab)
• Vasculitis (Etanercept)
• Lichenoid drug eruption (all three)
• Sarcoidosis & drug induced lupus rarely
• ACD can occur
• Slightly increased risk of non melanoma skin
cancer (esp if taken Mtx)

39. In a nut
shell
Small soluble polypeptide
mediators – pivotal role –
communication b/n cells
• Pleiotropism & Redundancy
• Primary & Secondary CKs
• T cell subsets- Th1, Th2, Th12, Treg
• Signal transduction pathways: NF-kB & Jak-STAT
• 8 CK receptor families:
 Haematopoietin receptor- common chain:
 𝛾c - IL-2 & 15 , IL-4 & 13 , IL-9 & 21, IL- 7 & TSLP

40. Class 2- IFN & IL-10
TNF- TNF β, LT-⍺
IL-1 – IL-1⍺, 1β, 18 & 33
TGF β family
IL-17
Chemokines
 βc – IL-2 & 15
 IL-3Rβ - IL-3,5, GM-CSF
 IL-12Rβ2 - IL-12,23
 Gp 130- IL-6,11,27,
Oncostatin M
In a nut
shell

41. • Psoriasis- Th1 & Th 17
• AD - Th2
• BP - Th2
• Biologicals- Anti TNF⍺, AntiIL-1, anti- IL-6, Th-17
• Adverse reactions to CKs
In a nut
shell

42. Thank
you!
“For not falling
asleep”