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cIAP1/2–TRAF2–SHP-1–Src–MyD88 Complex Regulates Lipopolysaccharide-Induced IL-27 Production through NF-κB Activation in Human Macrophages
- Source :
- The Journal of Immunology. 200:1593-1606
- Publication Year :
- 2018
- Publisher :
- The American Association of Immunologists, 2018.
-
Abstract
- The inhibitors of apoptosis (IAP) proteins, initially described in the context of apoptosis regulation as promoting cell survival, have recently emerged as key regulators of innate immune signaling. As a result, downregulation of IAP via Smac mimetics (SMM) has both survival and immunoregulatory effects. IAPs modulate cytokine production in murine models either as a single agent or in response to LPS. However, the role of SMM and the involvement of IAPs in primary human cells and in particular macrophages with respect to cytokine production and innate immune responses remain largely unknown. IL-27, a member of the IL-12 cytokine family produced by APCs such as macrophages, has broad immunoregulatory properties in both innate and adaptive immune responses. Herein, we show that cellular IAPs (cIAPs) positively regulate LPS-induced IL-27 production in both primary human monocytes and macrophages. Investigations for the signaling mechanism of cIAPs involvement in IL-27 production in human macrophages revealed that LPS-induced IL-27 production is regulated by a novel signaling complex comprising cIAP1/2, TNFR-associated factor 2 (TRAF2), SHP-1, Src, and MyD88 leading to p38, c-Jun N-terminal kinases (JNK) and Akt activation and NF-κB signaling. In cancer cells, SMM induce the production of cytokines by activating the noncanonical alternate NF-κB pathway. However, in human macrophages, SMM do not induce the production of TNF-α and other cytokines while inhibiting LPS-induced IL-27 production by inhibiting the classical NF-κB pathway. These signaling pathways may constitute novel therapeutic avenues for immune modulation of IL-27 and provide insight into the modulatory immune effects of SMM.
- Subjects :
- Lipopolysaccharides
0301 basic medicine
TRAF2
p38 mitogen-activated protein kinases
medicine.medical_treatment
Proto-Oncogene Proteins pp60(c-src)
Immunology
Adaptive Immunity
Monocytes
Inhibitor of Apoptosis Proteins
03 medical and health sciences
Immune system
medicine
Humans
Immunology and Allergy
Protein kinase B
Cells, Cultured
Adaptor Proteins, Signal Transducing
Innate immune system
Tumor Necrosis Factor-alpha
Chemistry
Interleukins
Macrophages
Protein Tyrosine Phosphatase, Non-Receptor Type 6
NF-kappa B
TNF Receptor-Associated Factor 2
Baculoviral IAP Repeat-Containing 3 Protein
Immunity, Innate
Cell biology
030104 developmental biology
Cytokine
Gene Expression Regulation
Myeloid Differentiation Factor 88
Signal transduction
Signal Transduction
Proto-oncogene tyrosine-protein kinase Src
Subjects
Details
- ISSN :
- 15506606 and 00221767
- Volume :
- 200
- Database :
- OpenAIRE
- Journal :
- The Journal of Immunology
- Accession number :
- edsair.doi.dedup.....76f1a46b3313bc9085e45bb5baa7e0ed