Functional Roles of p38 Mitogen-Activated Protein Kinase in Macrophage-Mediated Inflammatory Responses

Abstract

Inflammation is a natural host defensive process that is largely regulated by macrophages during the innate immune response. Mitogen-activated protein kinases (MAPKs) are proline-directed serine and threonine protein kinases that regulate many physiological and pathophysiological cell responses. p38 MAPKs are key MAPKs involved in the production of inflammatory mediators, including tumor necrosis factor-α (TNF-α) and cyclooxygenase-2 (COX-2). p38 MAPK signaling plays an essential role in regulating cellular processes, especially inflammation. In this paper, we summarize the characteristics of p38 signaling in macrophage-mediated inflammation. In addition, we discuss the potential of using inhibitors targeting p38 expression in macrophages to treat inflammatory diseases.

Regulation of the maturation of human monocytes into immunosuppressive macrophages

“…These results confirm and extend those of murine studies documenting a role for the p38 MAPK pathway in the generation of MAC suppress 47,48 but are inconsistent with data suggesting that p38 MAPK expression is required for the generation of MAC inflam . 49,50 Because p38 MAPK is an upstream mediator of PTGS2, 51 current findings suggest that M-CSF and PAM3 use the p38 MAPK-PTGS2 axis to influence monocyte maturation. The expression of ERK, JNK, and MAP3K8 were upregulated in human monocytes treated with PAM3 but not M-CSF ( Figure 6B-C).…”

Mitogen-Activated Protein Kinase Signal Transduction in Solid Tumors

“…Also, inflammation-related molecule COX-2 may be over-expressed in prostate cancer, COX-2 can be a transcription factor involved in inflammation-mediated stem cell proliferation (Park et al, 2013) (mainly via prostaglandin E2 (PGE2) (Thanan et al, 2012;Dixon et al, 2013), while in turn, inhibition of COX-2 by lasiodin could down-regulate the MAPK signaling pathways , which finally reduced bladder carcinogenesis (Thanan et al, 2012). The p38 MAPK signaling is proved to be essential in inflammation, perhaps by regulating the function of macrophages (Yang et al, 2014), in some of these cancers, cytokine IL-6 and IL6-R which function in activation of inflammatory and androgen receptor (AR) are up-regulated (Sfanos et al, 2012). In other conditions, IL-6 also activates JAK family tyrosine kinases, which in turn activate multiple pathways through signaling molecules MAPK (Ara et al, 2010;.…”

Attenuation of the macrophage inflammatory activity by TiO2 nanotubes via inhibition of MAPK and NF-κB pathways

“…[1][2][3] Among the existing signaling pathways, mitogenactivated protein kinase (MAPK) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathways are key regulators of the inflammatory processes. 4,5 These pathways are known to be involved in the pro-inflammatory mediator expression induced by lipopolysaccharide (LPS), having a critical role in the regulation of cellular growth and differentiation as well as in controlling the cell behavior toward cytokines and stress stimuli. 6 LPS-evoked signaling leads to the activation of these signal transduction pathways, in either a myeloid differentiation factor 88-dependent…”

“…8,9 p38 MAPK is a key player in the inflammatory responses and is involved in stress-induced gene expression. 5,10,11 In addition, p38 is rapidly activated after LPS stimulation and was suggested to have an important role in controlling the expression of tumor necrosis factor (TNF)-α and inducible nitric oxide synthase (iNOS). 12 Similarly, ERK and JNK kinases are also known as stress-activated proteins and are involved in LPS-induced macrophage responses, increasing the production of proinflammatory cytokines and iNOS.…”