1 Dual regulatory roles of the phosphatidylinositol 3-kinase in interferon signaling

Kaur, Surinder; Sassano, Antonella; Joseph, Ajith M.; Majchrzak-Kita, Beata; Eklund, Elizabeth A.; Fish, Eleanor N.; Verma, Amit; Brachmann, Saskia M.; Platanias, Leonidas C.

doi:10.1016/j.cyto.2008.07.041

Cited by 1 publication

(1 citation statement)

References 46 publications

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“…Concerning the role of PI3K, our results were consistent with a previous study reporting that CXCL10 expression was defective in the absence of PI3K regulatory subunits in embryonic fibroblasts from p85 knockout mice. 29 Another report also showed that CXCL10 production in Mycobacterium bovis BCG-infected epithelial cells was PI3K dependent. 30 Taken together, our findings bring new insights on how protein aggregates could induce dendritic cells activation.…”

Section: Discussionmentioning

confidence: 96%

Growth Hormone Aggregates Activation of Human Dendritic Cells Is Controlled by Rac1 and PI3 Kinase Signaling Pathways

Nabhan

Gallais

Pallardy

et al. 2020

Journal of Pharmaceutical Sciences

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The presence of protein aggregates in biological products is suggested to promote immunogenicity, leading to the production of anti-drug antibodies with neutralizing capacities. This suggests a CD4 þ T-cell dependent adaptive immune response, thus a pivotal role for antigen-presenting cells, such as dendritic cells (DCs). We previously showed that human growth hormone aggregates induced DC maturation, with notably an increase in CXCL10 production. DC phenotypic modifications were sufficient to promote allogeneic CD4 þ T-cell proliferation with Th1 polarization. In this work, we identified the main intracellular signaling pathways involved in DC activation by human growth hormone aggregates, showing that aggregates induced p38 mitogen-activated protein kinase, extracellular signaleregulated kinase, and c-Jun N-terminal kinase phosphorylation, as well as nuclear factor kB subunit p65 nuclear translocation. Next, investigating the implication of Rho GTPases and phosphoinositide 3-kinase (PI3K) in activated DC showed that Rac1 and Cdc42 regulated the phosphorylation of MAP kinases, whereas PI3K was only implicated in c-Jun N-terminal kinase phosphorylation. Furthermore, we showed that Rac1 and PI3K pathways, but not Cdc42, regulated the production of CXCL10 via the MAP kinases and nuclear factor kB. Taken together, our results bring new insight on how protein aggregates could induce DC activation, leading to a better understanding of aggregates role in therapeutic proteins immunogenicity.

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Section: Discussionmentioning

confidence: 96%