Activation of ERK1/2 and TNF-α production are regulated by calcium/calmodulin signaling pathway during Penicillium marneffei infection within human macrophages

• Effect of Ca2+ on activation of ERK1/2 in macrophages stimulated by P. marneffei.
• CaM is required for P. marneffei-induced activation of ERK1/2.
• Role of CaMKII in P. marneffei-induced activation of ERK1/2.
• Effect of the CaM/CaMKII pathway on TNF-α production.

Previous study have shown that Penicillium marneffei (P. marneffei)-induced TNF-α production via an extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase-dependent mechanism is an important host defence mechanism against P. marneffei in human macrophages. Therefore, we explore signaling pathway that regulates TNF-α secretion and activation of ERK1/2 by intracellular signaling mechanisms during P. marneffei infection. We found that ERK1/2 activation was dependent on the calcium/calmodulin/calmodulin kinase Ⅱ pathway in P. marneffei-infected human macrophages. In contrast, P. marneffei-induced p38 MAPK activation was negatively regulated by calcium/calmodulin/calmodulin kinase Ⅱ signaling pathway. Furthermore, TNF-α production in P. marneffei-infected human macrophages was also dependent on Ca2+/calmodulin/calmodulin kinase Ⅱ pathway. These data suggest that Ca2+/calmodulin/calmodulin kinase Ⅱ pathway plays vital regulatory roles in macrophage activation and subsequent cytokine production during P. marneffei infection.