Neurocysticercal antigens stimulate chemokine secretion from human monocytes via an NF-kappaB-dependent pathway.
Neurocysticercosis, infection with larval Taenia solium, is a common, serious neuroparasitic infection. Larval degeneration results in inflammatory cell influx and granuloma formation which leads to clinical symptomatology. The role of chemokines in such cell influx is unknown. We demonstrate that monocyte stimulation by T. solium larval antigen (TsAg) results in a differential profile of CXCL8/IL-8 (146.5+/-8.5ng/ml after 24h), CCL2/MCP-1 (267+/-4 ng/ml after 48 h) and CCL3/MIP-1alpha (1.72+/-0.43 ng/ml after 8 h) secretion. There was coordinate mRNA accumulation reaching maximum at 1h for CCL3 and 2 h for CXCL8 and CCL2. TsAg induced maximal nuclear binding of p65, p50 and c-rel subunits of the transcriptional regulator NF-kappaB by 2 h. IkappaBalpha but not IkappaBbeta was degraded within 10 min before resynthesis by 2 h. Pre-treatment with the broad-spectrum NF-kappaB inhibitor pyrrolidine dithiocarbamate caused complete abrogation of TsAg-induced CCL2 secretion (p=0.005) and 91% reduction of CXCL8 secretion (p=0.0003). TsAg was unable to induce CXCL8 promoter activity in Toll-like receptor (TLR)-2 or TLR-4/MD-2 transfected HeLa cells in the absence of lectins or other adaptor molecules. In summary, our data demonstrate that TsAg induces chemokine secretion via specific pathways dependent on NF-kappaB but not TLR-4/TLR-2, and indicate a potential mechanism whereby larval degeneration results in brain inflammation.
Uddin
Jasim
J
Department of Infectious Diseases and Immunity, Faculty of Medicine and Wellcome Trust Centre for Clinical Tropical Medicine, Imperial College, Hammersmith Hospital, London, UK.
Gonzalez
Armando E
AE
Gilman
Robert H
RH
Garcia
Hector H
HH
Verastegui
Manuela
M
Moore
Lisa J
LJ
Evans
Carlton A W
CA
Read
Robert C
RC
Friedland
Jon S
JS
D000818:Animals; D000947:Antigens, Helminth / Q000276:immunology*; D002467:Cell Nucleus / Q000737:chemistry; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000378:metabolism; D018925:Chemokines / Q000235:genetics / Q000378:metabolism*; D019743:Chemokines, CXC / Q000235:genetics / Q000378:metabolism; D003552:Cysticercus / Q000276:immunology*; D015870:Gene Expression; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D016209:Interleukin-8 / Q000096:biosynthesis; D009000:Monocytes / Q000276:immunology* / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D052002:NF-kappa B p50 Subunit / Q000378:metabolism*; D011759:Pyrrolidines / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D013552:Swine; D013859:Thiocarbamates / Q000494:pharmacology; D051193:Toll-Like Receptors / Q000502:physiology; D051996:Transcription Factor RelA / Q000378:metabolism*
D000947:Antigens, Helminth; C111835:CCL2 protein, human; C508606:CXCL8 protein, human; D018932:Chemokine CCL2; D018925:Chemokines; D019743:Chemokines, CXC; D020672:I-kappa B Proteins; D016209:Interleukin-8; D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; C000606204:NFKBIA protein, human; D011759:Pyrrolidines; D012333:RNA, Messenger; D013859:Thiocarbamates; D051193:Toll-Like Receptors; D051996:Transcription Factor RelA; D000072000:NF-KappaB Inhibitor alpha; C020972:pyrrolidine dithiocarbamic acid