The adenylyl cyclase-cAMP system suppresses TARC/CCL17 and MDC/CCL22 production through p38 MAPK and NF-kappaB in HaCaT keratinocytes.
Patients with atopic dermatitis (AD) have significantly reduced plasma cAMP levels, and the cAMP level is correlated with the immunopathogenesis of AD. The production of thymus and activation-regulated chemokine (TARC/CCL17) and macrophage-derived chemokine (MDC/CCL22) in keratinocytes is significantly enhanced in patients with AD. In the present study, we investigated the in vitro effects of the adenylyl cyclase-cAMP system on IFN-gamma and TNF-alpha-stimulated production of TARC and MDC in human HaCaT keratinocytes. Both forskolin (a direct activator of adenylyl cyclase) and dibutyryl-cAMP (DBcAMP, a permeable analog of cAMP) suppressed production of TARC and MDC in parallel with the activation of NF-kappaB in IFN-gamma and TNF-alpha-stimulated HaCaT cells. Moreover, inhibition of NF-kappaB suppressed TARC and MDC production induced by IFN-gamma plus TNF-alpha. However, dideoxyforskolin, a forskolin derivative that does not activate cAMP, failed to suppress the secretion of these chemokines. An inhibitor of p38 MAPK suppressed the production of TARC and MDC in parallel to the activation of NF-kappaB in HaCaT cells. Of note, the IFN-gamma plus TNF-alpha-stimulated activation of p38 MAPK was suppressed following incubation with forskolin or DBcAMP alone. These results indicate that the adenylyl cyclase-cAMP system has an inhibitory role in IFN-gamma plus TNF-alpha-stimulated production of TARC and MDC in HaCaT keratinocytes by inhibiting NF-kappaB activation through p38 MAPK pathway, implying that the adenylyl cyclase-cAMP system could be a candidate therapeutic target of Th2-skewed skin inflammation such as AD.
Department of Environmental Medical Biology, Wonju College of Medicine, Yonsei University, Wonju, Gangwon 220-701, Republic of Korea.
Xu-Feng
XF
Qi
Dong-Heui
DH
Kim
Yang-Suk
YS
Yoon
Jian-Hong
JH
Li
Soon-Bong
SB
Song
Dan
D
Jin
Xue-Zhu
XZ
Huang
Yung-Chien
YC
Teng
Kyu-Jae
KJ
Lee
D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000262:Adenylyl Cyclases / Q000378:metabolism*; D003994:Bucladesine / Q000494:pharmacology; D054414:Chemokine CCL17 / Q000096:biosynthesis*; D054422:Chemokine CCL22 / Q000096:biosynthesis*; D005576:Colforsin / Q000031:analogs & derivatives / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D015603:Keratinocytes / Q000187:drug effects / Q000201:enzymology*; D018448:Models, Immunological; D016328:NF-kappa B / Q000378:metabolism*; D050794:STAT1 Transcription Factor / Q000378:metabolism; D013873:Thionucleotides / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
C105593:8-bromoadenosine-3',5'-cyclic monophosphorothioate; C106230:CCL17 protein, human; C515482:CCL22 protein, human; D054414:Chemokine CCL17; D054422:Chemokine CCL22; D016328:NF-kappa B; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D013873:Thionucleotides; D014409:Tumor Necrosis Factor-alpha; C017759:9-(tetrahydro-2-furyl)-adenine; D005576:Colforsin; D015124:8-Bromo Cyclic Adenosine Monophosphate; D003994:Bucladesine; D007371:Interferon-gamma; D000242:Cyclic AMP; D048051:p38 Mitogen-Activated Protein Kinases; D000262:Adenylyl Cyclases; D000225:Adenine; C047983:1,9-dideoxyforskolin