2. Introduction
▪ Signal transduction derived from “transduce” meaning to lead across
▪ Extracellular signalling molecule activates receptor thus creates a ‘response’
▪ Various processes coordinates individual cells to support the organism as a whole
▪ Hormones, Growth factors, Cytokines, physiological molecules, drugs
▪ Diseases like diabetes, psoriasis arise from defective pathways remains area of research
3. Some Basic Terminologies
▪ Receptor: Protein molecules receives chemical signal from outside the cell, e.g- G- protein
coupled receptor, Glucocorticoid receptor
▪ Ligand: Ion / molecules (functional) group binds with the receptor ,serving biological
purpose, e.g- hormones, drugs, ions etc
▪ Second messenger: Intra- cellular signaling molecules released by the cells to trigger
physiological changes, e.g- c- AMP, c- GMP, IP3, DAG, Calcium
9. Applied Aspects:
When C-AMP pathway is dysregulated-can influence the pathogenesis of inflammatory
cutaneous diseases e.g- Psoriasis, Atopic dermatitis
In these diseases c-AMP & it’s effector protein (PKA) are downregulated
So elevation of c-AMP may be a therapeutic option
Apremilast: a selective PDE4 inhibitor, inhibits the pro-inflammatory cytokines e.g- TNF@,
IFN y, IL-12, IL-17, IL-23
CRISABOROL: a PDE4 inhibitor
Other drugs: - E 6005,
-LEO 29102,
-Roflumilast,
-Isoxazoline derivative ( PDE4/PDE7 inhibitor)
10. ▪ PDE4 inhibitors in other Inflammatory skin disease:
- Lichen planus
- DLE
- Cutaneous sarcoidosis
Levy J, Zhou DM, Zippin JH (2016) Cyclic Adenosine Monophosphate Signaling in Inflammatory Skin Disease. J Clin Exp
Dermatol Res 7: 326. doi:10.4172/2155-9554.1000326
12. Transmembrane enzyme linked receptor
signalling
▪ Insulin acts through this pathway
▪ Growth factors, cytokines, ANF acts through above mentioned pathway
▪ Biological agents:
a. Alefacept- a receptor –Ab fusion protein, LFA 3 & Fc IgG 1, bindind site- CD2, in
moderate- severe psoriasis
b. Efalizumab: Human monoclonal Ab,human IgG1, binding site- CD 11a & LFA 1, in mod-
severe psoriasis
c. Adalimumab: Human monoclonal Ab, IgG1, binding site- TNF@, used in- psoriasis,
severe psoriatic arthritis, RA, AS, CD
d. Etanercept: Receptor –Ab fusion protein, binding site TNF@, in Psoriasis, psoriatic
arthritis, AS, RA
e. Infliximab: chimeric monoclonal Ab, binds to TNF @, in Psoriasis, psoriatic arthritis, RA,
AS, UC, CD
13. ▪ Etolizumab: a novel anti CD6 monoclonal antibody- in mod- severe chronic plaque
psoriasis
▪ IVIg: composed of > 90% IgG, minimal amount of IgA, sol. CD4, CD8, HLA molecules,
cytokines
16. JAK- STAT pathway
▪ Components- 1. Receptor
2. Ligands- prolactin ,EPO, thrombopoietin,IFN,ILs
JAK- Janus Kinase – is an enzyme uses ATP to phosphorylates other proteins
4 types- JK1,JK2,JK3 & Tyrosine kinase 2
STAT: signal transducer + activator of transcription
JAK 2 mutation: most important, seen in-
a. Chronic myeloproliferative disorder
b. Polycythemia Vera
c. Essential Thrombocytopenia
d. Myelofibrosis
Surprisingly not seen in CML
In hyper-IgE syndrome: STAT-3 Mutation
17. JAK- STAT pathway
▪ Tofacitinib, filgotinib—JAK3 inhibitor—clinical trials
▪ Cytokines play key roles in controlling cell growth and the immune response via cytokine
receptors which in turn rely on the JAK enzymes for signal transduction
▪ Hence drugs that inhibit the activity of these Janus kinases block cytokine signalling
▪ Under development for the treatment of psoriasis, vitiligo, rheumatoid
arthritis, polycythemia vera, essential thrombocythemia , ulcerative colitis, myeloid
metaplasia , myelofibrosis
▪ Roxolitinib- a Janus Kinase inhibitor- tried in sepsis due to Candida albicans
22. References
▪ Bolognia, 3rd edition
▪ Goodman & Gillman’s The Pharmacological basis of Therapeutics-
12th ed.
▪ Essential of Medical pharmacology, 7th Ed. By K.D. Tripathi
▪ Ganong’s Review of Medical Physiology, 25th Ed.by Kim E. Barrett
▪ Levy J, Zhou DM, Zippin JH (2016) Cyclic Adenosine
Monophosphate Signaling in Inflammatory Skin Disease. J Clin Exp
Dermatol Res 7: 326. doi:10.4172/2155-9554.1000326
▪ Internet
