IP-10 mRNA expression in cultured keratinocytes is suppressed by inhibition of protein kinase-C and tyrosine kinase and elevation of cAMP.
IFN-gamma-inducible protein-10 (IP-10) is a chemokine, which plays an important role in mediating inflammation by attracting activated T cells, and it has been demonstrated in inflammatory skin diseases and cutaneous T cell lymphomas. Keratinocytes can abundantly produce IP-10 mRNA after IFN-gamma treatment. In this study we explored possibilities to downregulate IP-10 expression using human cultured keratinocytes as a model system. Decreased IP-10 mRNA levels were found using specific inhibitors of protein kinase (PK)-C (H-7 and Calphostin C). Moreover, depletion of PK-C by pretreatment of the cells with phorbol myristate (PMA) also down-regulated IP-10 mRNA expression. In addition, elevated cAMP levels were shown to inhibit IP-10 mRNA expression as could be concluded from experiments with forskolin and W-7, substances which, directly or indirectly, raise the intracellular cAMP level. With Genistein, an inhibitor of tyrosine kinase, the IFN-gamma-induced IP-10 mRNA expression was also found to be diminished. These data suggest that inhibitors of the IP-10 mRNA expression in cultured keratinocytes may be potentially of clinical relevance to suppress inflammatory processes in the skin.
Department of Dermatology, University Hospital Vrije Universiteit, Amsterdam, The Netherlands.
D M
DM
Boorsma
J
J
Flier
E N
EN
van den Brink
S
S
Sampat
H L
HL
Walg
R
R
Willemze
C P
CP
Tensen
T J
TJ
Stoof
D002478:Cells, Cultured; D054357:Chemokine CXCL10; D019743:Chemokines, CXC / Q000235:genetics*; D000242:Cyclic AMP / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism*; D008297:Male; D011493:Protein Kinase C / Q000037:antagonists & inhibitors* / Q000502:physiology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism*
D054357:Chemokine CXCL10; D019743:Chemokines, CXC; D012333:RNA, Messenger; D000242:Cyclic AMP; D011505:Protein-Tyrosine Kinases; D011493:Protein Kinase C