Roles of p38 Mitogen-Activated Protein Kinase, NF-κB, and Protein Kinase C in Proinflammatory Cytokine mRNA Expression by Human Peripheral Blood Leukocytes, Monocytes, and Neutrophils in Response toAnaplasma phagocytophila

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Abstract
Anaplasma phagocytophila, an obligately intracellular bacterium of granulocytes, causes human granulocytic ehrlichiosis. Within 2 h after addition ofA. phagocytophila, interleukin-1β (IL-1β), tumor necrosis factor alpha (TNF-α), and IL-6 mRNAs are induced in human peripheral blood leukocytes (PBLs) or monocytes in vitro. However, neutrophils generate only IL-1β mRNA. In the present study, signaling pathways for induction of these three cytokines were examined. TNF-α and IL-6 mRNA expression by PBLs was inhibited with SB 203580 (a p38 mitogen-activated protein kinase [MAPK] inhibitor), MG-132 (a proteasome inhibitor), and SN-50 (an NF-κB inhibitor). Activation of p38 MAPK and NF-κB mRNAs in monocytes was detectable within 15 to 30 min after addition ofA. phagocytophila. Expression of these two cytokine mRNAs in PBLs and monocytes was also dependent on protein kinase C (PKC), protein kinase A (PKA), and protein tyrosine kinase (PTK). IL-1β mRNA expression by neutrophils was not dependent on p38 MAPK, and p38 MAPK was not activated in neutrophils incubated withA. phagocytophila. IL-1β mRNA induction by PBLs, monocytes, and neutrophils was dependent on PKC and PKA. Neutrophil expression of IL-1β mRNA was dependent on transglutaminase, phospholipase C, and PTK, all of which are also required for internalization ofA. phagocytophila. However, monocyte expression of IL-1β mRNA was less dependent on these enzymes. These results suggest thatA. phagocytophilatransduces different signals between its host neutrophils and monocytes for proinflammatory cytokine generation.

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