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Importance of phosphoinositide binding by human β‐defensin 3 for Akt‐dependent cytokine induction
Author(s) -
Phan Thanh Kha,
Lay Fung T,
Hulett Mark D
Publication year - 2018
Publication title -
immunology and cell biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.999
H-Index - 104
eISSN - 1440-1711
pISSN - 0818-9641
DOI - 10.1111/imcb.1017
Subject(s) - microbiology and biotechnology , pi3k/akt/mtor pathway , protein kinase b , signal transduction , proinflammatory cytokine , chemokine , biology , cytokine , innate immune system , chemotaxis , phospholipase c , phosphoinositide 3 kinase , receptor , chemistry , immunology , inflammation , biochemistry
Host defense peptides ( HDP s) are well‐characterized for their antimicrobial activities but also variously display potent immunomodulatory effects. Human β‐defensin 3 ( HBD ‐3) belongs to a well‐known HDP family known as defensins and is able to induce leukocyte chemotactic recruitment, leukocyte activation/maturation, proinflammatory cytokine release, and co‐stimulatory marker expression. HBD ‐3‐stimulated cytokine induction is NF ‐κB‐dependent and was initially suggested to act via G protein‐coupled C‐C chemokine receptor phospholipase C ( PLC ) and/or Toll‐like receptor signaling. Subsequent pharmacological inhibition, however, revealed that NF ‐κB activation by HBD ‐3 is receptor‐independent and instead involves the phosphoinositide 3‐kinase ( PI 3K)‐protein kinase B (Akt) pathway, the mechanism of which remains undetermined. Recently, we have shown that HBD ‐3 can enter mammalian cells and bind to inner membrane phosphoinositide 4,5‐bisphosphate [ PI (4,5)P 2 ], an important second lipid messenger of PLC and PI 3K‐Akt pathways. In this study, we report that the interaction of HBD ‐3 with PI (4,5)P 2 is important for PI 3K‐Akt‐ NF ‐κΒ‐mediated induction of tumor necrosis factor and interleukin‐6. These data provide insights into the mechanism of immunomodulation by HBD ‐3, and more generally, highlight the complex multifaceted signaling roles of HDP s in innate defense. Furthermore, it is suggested that the proposed mode of action may be conserved in other HDP s.