The mycobacterial 38-kilodalton glycolipoprotein antigen activates the mitogen-activated protein kinase pathway and release of proinflammatory cytokines through Toll-like receptors 2 and 4 in human monocytes.
Although the 38-kDa glycolipoprotein of Mycobacterium tuberculosis H37Rv is known to evoke prominent cellular and humoral immune responses in human tuberculosis (TB), little information is known about intracellular regulatory mechanisms involved in 38-kDa antigen (Ag)-induced host responses. In this study, we found that purified 38-kDa glycolipoprotein activates mitogen-activated protein kinases (MAPKs; extracellular signal-regulated kinase 1/2 [ERK1/2] and p38) and induces tumor necrosis factor alpha (TNF-alpha) and interleukin 6 (IL-6) in human monocytes. When the 38-kDa Ag was applied to monocytes from TB patients and healthy controls, the activation of ERK1/2 and p38 MAPK and the subsequent cytokine secretion were greater in the monocytes from the active pulmonary TB patients than in monocytes from the healthy controls. Additionally, neutralizing antibodies for Toll-like receptor 2 (TLR2) or TLR4 significantly reduced the ERK1/2 and p38 activation induced by the 38-kDa protein when the antibodies were applied to HEK293 cells overexpressing TLR2 or TLR4 as well as human primary monocytes. Furthermore, the inhibition of TLR2 significantly, and that of TLR4 partially, decreased the 38-kDa Ag-induced secretion of TNF-alpha and IL-6 in human monocytes. The intact protein moieties of the 38-kDa protein were responsible for biologic activities by this Ag. These data collectively demonstrate that the 38-kDa glycolipoprotein, acting through both TLR2 and TLR4, induces the activation of the ERK1/2 and p38 MAPK pathways, which in turn play an essential role in TNF-alpha and IL-6 expression during mycobacterial infection.
Jung
Saet-Byel
SB
Department of Microbiology, College of Medicine, Chungnam National University, 6 Munhwa-dong, Jungku, Daejeon 301-747, South Korea.
Yang
Chul-Su
CS
Lee
Ji-Sook
JS
Shin
A-Rum
AR
Jung
Sung-Soo
SS
Son
Ji Woong
JW
Harding
Clifford V
CV
Kim
Hwa-Jung
HJ
Park
Jeong-Kyu
JK
Paik
Tae-Hyun
TH
Song
Chang-Hwa
CH
Jo
Eun-Kyeong
EK
D000942:Antigens, Bacterial / Q000502:physiology*; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis; D020935:MAP Kinase Signaling System / Q000502:physiology*; D009000:Monocytes / Q000276:immunology*; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D010766:Phosphorylation; D051195:Toll-Like Receptor 2 / Q000502:physiology*; D051197:Toll-Like Receptor 4 / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology
D000942:Antigens, Bacterial; D016207:Cytokines; D015850:Interleukin-6; C495342:TLR2 protein, human; C495345:TLR4 protein, human; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases