Macrophage L-type Ca2+ channel antagonists alter Chlamydia pneumoniae MOMP and HSP-60 mRNA gene expression, and improve antibiotic susceptibility.
Recent data have shown a unique relationship between Ca2+ signaling in macrophages through L-type channels and the outcome of C. pneumoniae infection of such cells. The present investigation seeks to provide insights into the manner in which macrophage L-type Ca2+ channel operation affects major outer membrane protein (MOMP) and heat shock protein-60 (HSP-60) mRNA gene expression (factors associated with Chlamydia chronicity), and the possible effect of this on antibiotic susceptibility. Intracellular calcium ([Ca2+]i) chelation using varying doses of 1,2-bis (o-aminophenoxy) ethane-N,N,N'N'--tetra acetic acid (acetoxymethyl) ester (BAPTA-AM) induced an increase in MOMP and a decrease in HSP-60 mRNA gene expression. L-type Ca2+ channel antagonists produced an identical but enhanced effect. Since these findings associate specialized Ca2+ channels to Chlamydia chronicity, it was important to determine Ca2+ channel effect on the usual antibiotic refractory form of C. pneumoniae in macrophages. Inhibition of macrophage L-type Ca2+ channel operation improved C. pneumoniae antibiotic susceptibility assessed by decreased inclusion counts or down-regulated MOMP and HSP-60 mRNA gene expression. These findings provide molecular insights into how specialized Ca2+ channels influence Chlamydia chronic course in macrophages and demonstrates a role for L-type Ca2+ channel inhibitors in enhanced C. pneumoniae susceptibility to antibiotic therapy.
Azenabor
Anthony A
AA
Department of Health Sciences, University of Wisconsin, Milwaukee, WI 53211, USA. aazenabo@uwm.edu
Chaudhry
Aziz U
AU
Yang
Shoua
S
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D001425:Bacterial Outer Membrane Proteins / Q000187:drug effects* / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020746:Calcium Channels, L-Type / Q000378:metabolism*; D020013:Calcium Signaling; D002460:Cell Line; D018834:Chaperonin 60 / Q000235:genetics / Q000378:metabolism*; D002614:Chelating Agents / Q000494:pharmacology; D016993:Chlamydophila pneumoniae / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D004533:Egtazic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D015870:Gene Expression; D008264:Macrophages / Q000378:metabolism / Q000382:microbiology*; D051379:Mice; D009543:Nifedipine / Q000037:antagonists & inhibitors; D009553:Nimodipine / Q000037:antagonists & inhibitors; D012333:RNA, Messenger / Q000378:metabolism
D000900:Anti-Bacterial Agents; D001425:Bacterial Outer Membrane Proteins; D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D018834:Chaperonin 60; D002614:Chelating Agents; D012333:RNA, Messenger; C101031:major outer membrane protein, Chlamydia pneumoniae; C070379:1,2-bis(2-aminophenoxy)ethane N,N,N',N'-tetraacetic acid acetoxymethyl ester; D004533:Egtazic Acid; D009553:Nimodipine; D009543:Nifedipine