Distinct Role of p38 and c-Jun N-Terminal Kinases in IL-10-Dependent and IL-10-Independent Regulation of the Costimulatory Molecule B7.2 in Lipopolysaccharide-Stimulated Human Monocytic Cells

• Published in: The Journal of immunology (1950) 2002-02, Vol.168 (4), p.1759-1769
• Main Authors: Lim, Wilfred, Ma, Wei, Gee, Katrina, Aucoin, Susan, Nandan, Devki, Diaz-Mitoma, Francisco, Kozlowski, Maya, Kumar, Ashok
• Format: Article
• Language: English
• Subjects: Antigens, CD - genetics; Antigens, CD - metabolism; B7-2 Antigen; Cells, Cultured; Dexamethasone - pharmacology; Down-Regulation; Enzyme Inhibitors - pharmacology; Humans; Imidazoles - pharmacology; Interleukin-10 - physiology; JNK Mitogen-Activated Protein Kinases; JNK protein; Lipopolysaccharides - pharmacology; MAP Kinase Kinase 4; MAP Kinase Signaling System - drug effects; Membrane Glycoproteins - genetics; Membrane Glycoproteins - metabolism; Mitogen-Activated Protein Kinase Kinases - genetics; Mitogen-Activated Protein Kinase Kinases - physiology; Mitogen-Activated Protein Kinases - antagonists & inhibitors; Mitogen-Activated Protein Kinases - physiology; Monocytes - drug effects; Monocytes - immunology; Mutation; NF-kappa B - metabolism; p38 Mitogen-Activated Protein Kinases; p38 protein; Promoter Regions, Genetic; Pyridines - pharmacology; Tumor Cells, Cultured
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.168.4.1759

The costimulatory molecule B7.2 (CD86) plays a vital role in immune activation and development of Th responses. The molecular mechanisms by which B7.2 expression is regulated are not understood. We investigated the role of mitogen-activated protein kinases (MAPK) in the regulation of B7.2 expression in LPS-stimulated human monocytic cells. LPS stimulation of human monocytes resulted in the down-regulation of B7.2 expression that could be abrogated by anti-IL-10 Abs. Furthermore, SB202190, a specific inhibitor of p38 MAPK, inhibited LPS-induced IL-10 production and reversed B7.2 down-regulation, suggesting that LPS-induced B7.2 down-regulation may be mediated, at least in part, via regulation of IL-10 production by p38 MAPK. In contrast to human promonocytic THP-1 cells that are refractory to the inhibitory effects of IL-10, LPS stimulation enhanced B7.2 expression. This IL-10-independent B7.2 induction was not influenced by specific inhibitors of either p38 or p42/44 MAPK. To ascertain the role of the c-Jun N-terminal kinase (JNK) MAPK, dexamethasone, an inhibitor of JNK activation, was used, which inhibited LPS-induced B7.2 expression. Transfection of THP-1 cells with a plasmid expressing a dominant-negative stress-activated protein/extracellular signal-regulated kinase kinase 1 significantly reduced LPS-induced B7.2 expression, thus confirming the involvement of JNK. To study the signaling events downstream of JNK activation, we show that dexamethasone did not inhibit LPS-induced NF-kappaB activation in THP-1 cells, suggesting that JNK may not be involved in NF-kappaB activation leading to B7.2 expression. Taken together, our results reveal the distinct involvement of p38 in IL-10-dependent, and JNK in IL-10-independent regulation of B7.2 expression in LPS-stimulated monocytic cells.