Chemically modified tetracycline (CMT)-3 inhibits histamine release and cytokine production in mast cells: possible involvement of protein kinase C
Chemically modified tetracycline (CMT)-3 inhibits histamine release and cytokine production in mast cells: possible involvement of protein kinase C
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DOI：
10.1007/s00011-005-1358-5
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发表时间：
2005-07-01
影响因子：
6.7
通讯作者：
Eklund, KK
中科院分区：
文献类型：
--
作者：
Sandler, C;Ekokoski, E;Eklund, KK
Objective: To find novel inhibitors of mast cell function we have studied the effect of a potent, non-antimicrobial, chemically modified tetracycline, CMT-3 or COL-3, on key functions of mast cells.Methods and Results: In the presence of 25 mu M CMT-3, the 48/80-induced histamine release from rat serosal mast cells was inhibited significantly, to 43.0 +/- 7.3 % of control. Similarily, the activation-induced secretion of TNF-alpha and IL-8 by HMC-1 cells were decreased in the presence of 25 mu M CMT3 to 13.5 +/- 4.1 % and 9.7 +/- 1.1 % of control, respectively. CMT-3 did not cause intracellular accumulation of TNF-alpha but instead it reduced the expression of TNF-alpha mRNA in HMC-1 cells. Moreover, CMT-3 was found to significantly inhibit the protein kinase C (PKC) activity with IC50 value of 31 mu M. CMT-3 inhibited effectively both human recombinant PKCalpha and PKCdelta isoforms. In comparison to doxycycline, CMT-3 was more effective as an inhibitor of both cytokine production and PKC activity.Conclusions: Considering the central role of PKC in mast cell activation, PKC inhibition could, at least partially, explain the observed inhibitory effects of CMT-3. The inhibition of the key proinflarnmatory functions of mast cells by CMT-3 suggests its potential clinical usefulness in the treatment of allergic and inflammatory disorders.
