Regulation of impaired protein kinase C signaling by chemokines in murine macrophages during visceral leishmaniasis.
The protein kinase C (PKC) family regulates macrophage function involved in host defense against infection. In the case of Leishmania donovani infection, the impairment of PKC-mediated signaling is one of the crucial events for the establishment of parasite into the macrophages. Earlier reports established that C-C chemokines mediated protection against leishmaniasis via the generation of nitric oxide after 48 h. In this study, we investigated the role of MIP-1alpha and MCP-1 in the regulation of impaired PKC activity in the early hours (6 h) of infection. These chemokines restored Ca2+-dependent PKC activity and inhibited Ca2+-independent atypical PKC activity in L. donovani-infected macrophages under both in vivo and in vitro conditions. Pretreatment of macrophages with chemokines induced superoxide anion generation by activating NADPH oxidase components in infected cells. Chemokine administration in vitro induced the migration of infected macrophages and triggered the production of reactive oxygen species. In vivo treatment with chemokines significantly restricted the parasitic burden in livers as well as in spleens. Collectively, these results indicate a novel regulatory role of C-C chemokines in controlling the intracellular growth and multiplication of L. donovani, thereby demonstrating the antileishmanial properties of C-C chemokines in the disease process.
Dey
Ranadhir
R
Department of Microbiology, Bose Institute, P1/12, C.I.T. Scheme VII-M, Kolkata-700 054, India.
Sarkar
Arup
A
Majumder
Nivedita
N
Bhattacharyya Majumdar
Suchandra
S
Roychoudhury
Kaushik
K
Bhattacharyya
Sandip
S
Roy
Syamal
S
Majumdar
Subrata
S
D000818:Animals; D019742:Chemokines, CC / Q000378:metabolism / Q000494:pharmacology*; D002633:Chemotaxis; D007893:Leishmania donovani; D007898:Leishmaniasis, Visceral / Q000201:enzymology / Q000276:immunology*; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology* / Q000469:parasitology; D051379:Mice; D008807:Mice, Inbred BALB C; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism*; D064546:Protein Kinase C beta; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D015398:Signal Transduction; D013154:Spleen / Q000166:cytology / Q000201:enzymology; D013481:Superoxides / Q000378:metabolism; D000099221:Protein Kinase C zeta
D019742:Chemokines, CC; D011493:Protein Kinase C; D064546:Protein Kinase C beta; D012333:RNA, Messenger; D013481:Superoxides; D000099221:Protein Kinase C zeta