2. Signal Transduction

3. HLA-DR stimulus specific receptor signal transductiontranscription translation proteins Receptor associating proteins Protein kinease pathways Translocation of transcription factors mRNA post- transcription

4. HLA-DR proteins Receptor associating proteins Protein kinease pathways Translocation of transcription factors mRNA Cytokines Chemokines Enzymes Mitogens Growth factors HSP LPS CpG-DNA (bacteria) HSP60  CD14/TLR4/p38  IL-6, IL-4 production protection of arthritis in animal, help cellular stress stimulus specific receptor signal transductiontranscription translation post- transcription

5. HLA-DR proteins Receptor associating proteins Protein kinease pathways Translocation of transcription factors mRNA TCR TNFR (I,II) IL-1R (I,II) CD-14 IL-6R OSM TLRs TLR4 RANKL TNFR – TNF receptor I, II OSM – Oncostatin M TLR – Toll-like receptor RANKL – receptor activating neuclear kappa B ligand stimulus specific receptor signal transductiontranscription translation post- transcription TNF- , IL-1 , IL-6 IFN, IL-4, IL-10, TGF

6. proteins Receptor associating proteins Protein kinease pathways Translocation of transcription factors mRNA CD3-mediated tyrosine kinase MAPK (TNF- , IL-1 , CD14, UV, irradiat.,heat ) P38 JNK ERK (mitogen, GF) IRAK (IL-1) Jaks (IL-6, IL-4) GRKs MAPK: mitogens-activated protein kinases JNKs: c Jun terminal kinase ERK: extracellular signal regulated kinase IRAK : IL-1R associated kinase Jaks: Janus tyroskin kinase GRKs: G protein-couple kinases stimulus specific receptor signal transductiontranscription translation post- transcription

7. HLA-DR proteins Receptor associating proteins Protein kinease pathways Translocation of transcription factors mRNA NF-  B: Nuclear factor - kappa B AP-1: Activating protein 1 STAT: signal transducers and activators of transcription NF-  B AP-1 IL-6 STAT IL-4 STAT stimulus specific receptor signal transductiontranscription translation post- transcription

8. HLA-DR proteins Receptor associating proteins Protein kinease pathways Translocation of transcription factors mRNA Genes Cytokines Groth factor MMP TIMP c-Jun c-Fos stimulus specific receptor signal transductiontranscription translation post- transcription

9. HLA-DR proteins Receptor associating proteins Protein kinease pathways Translocation of transcription factors mRNA CD3-mediated tyrosine kinase MAPK (TNF- , IL-1  ) P38 JNK ERK (mitogen, GF) IRAK (IL-1) Jaks (IL-6, IL-4) GRKs Cytokines Chemokines Enzymes Mitogens Growth factors HSP LPS CpG-DNA (bacteria) NF-  B AP-1 IL-6 STAT IL-4 STAT stimulus specific receptor signal transductiontranscription translation post- transcription Genes Cytokines Groth factor MMP TIMP c-Jun c-Fos TNF-  IL-1  IL-6 IFN, IL-4 IL-10, TGF RANKL

10. HLA-DR stimulus specific receptor signal transductiontranscription translation proteins Receptor associating proteins Protein kinease pathways Translocation of transcription factors mRNA post- transcription MAPK inhibitor Scio-469 (oral ) phase IIb MAPK inhibitor Scio-469 (oral ) phase IIb RANKL AMG162 Humanized Ab AMG162 Humanized Ab Antiresorptive during bone remodeling siRNA TNF blockade mouse model siRNA TNF blockade mouse model Calcineurin inhibitor Calcineurin inhibitor JNK inhibitor TRAF inhibitor