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Transcription factor AP-1 Runt-related transcription factor 1 T-cell surface glycoprotein CD3 zeta chain Inositol 1,4,5- trisphosphate receptor type 1 Interleukin-2 Interleukin 2 (IL-2) Receptor 1- phosphatidylinositol 4,5- bisphosphate phosphodiesterase gamma-1 Nuclear factor of activated T-cells Nuclear factor of activated T-cells Interleukin-2 Interleukin-2 ATP-binding cassette, sub-family B (MDR/TAP), member 1 Interleukin-2 Serine/threonine- protein phosphatase PP1-alpha catalytic subunit Peptidyl-prolyl cis-trans isomerase FKBP1A T-cell surface glycoprotein CD3 TCR complex T-cell-specific surface glycoprotein CD28 Serine/threonine- protein phosphatase PP1-alpha catalytic subunit Nuclear factor of activated T-cells Peptidyl-prolyl cis-trans isomerase FKBP1A Inositol 1,4,5- trisphosphate Ca+ Ca+ Tacrolimus Tacrolimus PIP(18:0/18:1(11Z)) DG(18:0/18:1(11Z)/0:0) Pi Calcium Ca+ Pi Tacrolimus IL-2 Promoter TCR Signalling mTOR signaling pathway Nuclear factor NF-kappa-B p105 subunit Activation, Differentiation and Migration of T Cells MHC/Antigen An antigen presenting cell like a dendritic cell or antigen activates the t cell receptor (TCR) complex, which includes the CD3 and CD28 receptor. TCR Signalling leads to IP3 production which leads to calcium levels to increase in the cell. Tacrolimus is taken orally or topically and absorbed into the blood. It enters T cells through ABC or SLC transporters like the ABCB1 transporter. Tacroblimus binds to FKBP12 to form a complex which inhibits calcineurin. It subsequently inhibits the dephosphorylation of of NFAT. NFAT is an important transcription protein for interleukin 2 (IL-2) production in T cells, so a lower concentration of NFAT being activated leads to lower IL-2 production. IL-2 is released outside the cell through vesicle packaging in the golgi apparatus. IL-2 can act in an autocrine or paracrine way once it is in the extracellular space. IL-2 interacts with interleukin-2 receptor on T-cells which leads to mTOR signalling. Decreased IL-2 production leads to less activation of receptors. mTOR signalling would lead to activation, differentiation and migration of T-cells, but reduced IL-2 would lead to decreased aforementioned activities. Nucleus Endoplasmic Reticulum Golgi Apparatus Cytosol
Nucleus Endoplasmic Reticulum JUN RUNX1 CD247 ITPR1 IL2 IL2RG PLCG1 NFATC3 NFATC3 IL2 IL2 ABCB1 IL2 PPP1CA FKBP1A CD3E TRB CD28 PPP1CA NFATC3 FKBP1A Inositol 1,4,5- trisphosphate Calcium Calcium Tacrolimus Tacrolimus PIP(18:0/18:1(11Z)) DG(18:0/18:1(11Z)/0:0) Phosphate Calcium Phosphate Tacrolimus IL-2 Promoter TCR Signalling mTOR signaling pathway NFKB1
JUN RUNX1 CD247 ITPR1 IL2 IL2RG PLCG1 NFATC3 NFATC3 IL2 IL2 ABCB1 IL2 PPP1CA FKBP1A CD3E TRB CD28 PPP1CA NFATC3 FKBP1A Inotp Ca+ Ca+ Tacroli Tacroli PIP36:1 DG36:1 Pi Ca2+ Ca+ Pi Tacroli IL-2 P TCR Sig PW076001