Engagement of CD14 Sensitizes Primary Monocytes to IFN-γ to Produce IL-12/23p40 and IL-23 Through p38 Mitogen-Activated Protein Kinase and Independent of the Janus Kinase/Signal Transducers and Activators of Transcription Signaling

2013 ◽  
Vol 33 (8) ◽  
pp. 434-445 ◽  
Author(s):  
Maria A. Blahoianu ◽  
Ali A.R. Rahimi ◽  
Niranjala Gajanayaka ◽  
Maya Kozlowski ◽  
Jonathan B. Angel ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Janus Kinase ◽  
Mitogen Activated Protein Kinase ◽  
Signal Transducers ◽  
Mitogen Activated Protein ◽  
Ifn Γ ◽  
Signal Transducers And Activators

scholarly journals Borrelia burgdorferi-Induced Expression of Matrix Metalloproteinases from Human Chondrocytes Requires Mitogen-Activated Protein Kinase and Janus Kinase/Signal Transducer and Activator of Transcription Signaling Pathways

2004 ◽  
Vol 72 (5) ◽  
pp. 2864-2871 ◽  
Author(s):  
Aruna K. Behera ◽  
Cheleste M. Thorpe ◽  
J. Michael Kidder ◽  
Wendy Smith ◽  
Ethan Hildebrand ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Janus Kinase ◽  
Lyme Arthritis ◽  
Mitogen Activated Protein Kinase ◽  
Cartilage Explants ◽  
Human Chondrocytes ◽  
Signal Transducer ◽  
Tnf Α ◽  
Mitogen Activated Protein ◽  
Infected Cells

ABSTRACT Elevations in matrix metalloproteinase 1 (MMP-1) and MMP-3 have been found in patients with Lyme arthritis and in in vitro models of Lyme arthritis using cartilage explants and chondrocytes. The pathways by which B. burgdorferi, the causative agent of Lyme disease, induces the production of MMP-1 and MMP-3 have not been elucidated. We examined the role of the extracellular signal-regulated kinase 1/2 (ERK1/2), c-Jun N-terminal kinase (JNK), p38 mitogen-activated protein kinase (MAPK) and the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathways in MMP induction by B. burgdorferi. Infection with B. burgdorferi results in rapid phosphorylation of p38 and JNK within 15 to 30 min. Inhibition of JNK and p38 MAPK significantly reduced B. burgdorferi-induced MMP-1 and MMP-3 expression. Inhibition of ERK1/2 completely inhibited the expression of MMP-3 in human chondrocytes following B. burgdorferi infection but had little effect on the expression of MMP-1. B. burgdorferi infection also induced phosphorylation and nuclear translocation of STAT-3 and STAT-6 in primary human chondrocytes. Expression of MMP-1 and MMP-3 was significantly inhibited by inhibition of JAK3 activity. Induction of MMP-1 and -3 following MAPK and JAK/STAT activation was cycloheximide sensitive, suggesting synthesis of intermediary proteins is required. Inhibition of tumor necrosis factor alpha (TNF-α) significantly reduced MMP-1 but not MMP-3 expression from B. burgdorferi-infected cells; inhibition of interleukin-1β (IL-1β) had no effect. Treatment of B. burgdorferi-infected cells with JAK and MAPK inhibitors significantly inhibited TNF-α induction, consistent with at least a partial role for TNF-α in B. burgdorferi-induced MMP-1 expression in chondrocytes.

scholarly journals Inhibition of Monocytic Interleukin-12 Production by Candida albicans via Selective Activation of ERK Mitogen-Activated Protein Kinase

2004 ◽  
Vol 72 (5) ◽  
pp. 2513-2520 ◽  
Author(s):  
Ningfeng Tang ◽  
Liming Liu ◽  
Kefei Kang ◽  
Pranab K. Mukherjee ◽  
Masakazu Takahara ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Protein Kinase ◽  
Inhibitory Activity ◽  
Biochemical Analysis ◽  
Specific Inhibitor ◽  
Mitogen Activated Protein Kinase ◽  
Interleukin 12 ◽  
Mitogen Activated Protein ◽  
Ifn Γ ◽  
Stimulating Factor

ABSTRACT Our previous data demonstrated that live Candida albicans inhibits interleukin-12 (IL-12) production by human monocytes. Here we explored whether C. albicans inhibits IL-12 via a released factor and whether the inhibition is mediated via mitogen-activated protein kinase (MAPK) regulation. Supernatant fluids were obtained from cultured C. albicans (SC5314) as well as cultured Saccharomyces cerevisiae after 20 h of incubation. At 2 h postincubation of monocytes with heat-killed C. albicans (HKCA) (2:1) to stimulate IL-12, concentrated fungal supernatant fluids were added and incubated for an additional 20 h. The present data show that, unlike supernatant fluids obtained from S. cerevisiae, the C. albicans supernatant fluids significantly suppressed IL-12 production induced by HKCA. This suggested that the inhibition is Candida specific. A preliminary biochemical analysis revealed that this secretory IL-12 inhibitory factor is glycoprotein in nature. The inhibitory activity had no effect on the phagocytosis of yeasts. Supernatant fluids from C. albicans markedly induced the phosphorylation of ERK44/42 MAPK, but not p38 and SAPK, 1 min after they were added to monocytes. To test if the induction of ERK44/42 MAPK was central to the IL-12 inhibition, we used gamma interferon (IFN-γ) (1 ng/ml) plus lipopolysaccharide (LPS) (100 ng/ml) to stimulate IL-12 production by monocytes. The inhibition of ERK MAPK by the specific inhibitor PD 98059 significantly reduced phospho-ERK44/42 MAPK levels induced by C. albicans supernatant fluids in the IFN-γ-plus-LPS-driven monocytes. Concomitantly, PD 98059 reversed the IL-12 inhibitory activity of the C. albicans supernatant (P < 0.01). These data indicate that C. albicans can inhibit IL-12 production by secreting an ERK44/42 MAPK-stimulating factor and thus can attenuate effective immune responses.

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