PMID- 26218692
OWN - NLM
STAT- MEDLINE
DCOM- 20151007
LR  - 20150729
IS  - 2163-0763 (Electronic)
IS  - 2163-0755 (Linking)
VI  - 79
IP  - 2
DP  - 2015 Aug
TI  - Discrete roles of intracellular phospholipases A2 in human neutrophil 
      cytotoxicity.
PG  - 238-46
LID - 10.1097/TA.0000000000000730 [doi]
AB  - BACKGROUND: The role of calcium-independent phospholipase A2 (iPLA2), a component 
      of the three major PLA2 families, in acute/chronic inflammatory processes remains 
      elusive. Previous investigations have documented iPLA2-mediated respiratory burst 
      of neutrophils (PMNs); however, the causative isoform of iPLA2 is unidentified. 
      We also demonstrated that the iPLA2gamma-specific inhibitor attenuates 
      trauma/hemorrhagic shock-induced lung injury. Therefore, iPLA2gamma may be implicated 
      in acute inflammation. In addition, arachidonic acid (AA), which is primarily 
      produced by cytosolic PLA2 (cPLA2), is known to display PMN cytotoxicity, 
      although the relationship between AA and the cytotoxic function is still being 
      debated on. We therefore hypothesized that iPLA2gamma regulates PMN cytotoxicity via 
      AA-independent signaling pathways. The study aim was to distinguish the role of 
      intracellular phospholipases A2, iPLA2, and cPLA2, in human PMN cytotoxicity and 
      explore the possibility of the presence of signaling molecule(s) other than AA. 
      METHODS: Isolated human PMNs were incubated with the PLA2 inhibitor selective for 
      iPLA2beta, iPLA2gamma, or cPLA2 and then activated with 
      formyl-methionyl-leucyl-phenylalanine (fMLP) or phorbol 12-myristate 13-acetate 
      (PMA). Superoxide production was assayed according to the superoxide 
      dismutase-inhibitable cytochrome c reduction method, and the degree of elastase 
      release was measured using a p-nitroanilide-conjugated elastase-specific 
      substrate. In addition, chemotaxis toward platelet activating factor/fMLP was 
      determined with a modified Boyden chamber system. RESULTS: The iPLA2gamma-specific 
      inhibitor reduced the fMLP/PMA-stimulated superoxide generation by 90% and 30%, 
      respectively; in addition, the inhibitor completely blocked the 
      fMLP/PMA-activated elastase release. However, the cPLA2-specific inhibitor did 
      not abrogate these effects to any degree at all concentrations. Likewise, the 
      inhibitor for iPLA2gamma, but not iPLA2beta or cPLA2, completely inhibited the platelet 
      activating factor/fMLP-induced chemotaxis. CONCLUSION: iPLA2 is involved in 
      extracellular reactive oxygen species production, elastase release, and 
      chemotaxis in response to well-defined stimuli. In addition, the ineffectiveness 
      of the cPLA2 inhibitor suggests that AA may not be relevant to these cytotoxic 
      functions.
FAU - Mikami, Saori
AU  - Mikami S
AD  - From the Department of Acute Critical Care and Disaster Medicine (S.M., M.K., 
      Y.O.), Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental 
      University; Trauma and Acute Critical Care Medical Center (J.A., K.M.), Medical 
      Hospital of Tokyo Medical and Dental University; and Department of Biology 
      (T.K.), Faculty of Science, Ochanomizu University, Tokyo, Japan.
FAU - Aiboshi, Junichi
AU  - Aiboshi J
FAU - Kobayashi, Tetsuyuki
AU  - Kobayashi T
FAU - Kojima, Mitsuaki
AU  - Kojima M
FAU - Morishita, Koji
AU  - Morishita K
FAU - Otomo, Yasuhiro
AU  - Otomo Y
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - J Trauma Acute Care Surg
JT  - The journal of trauma and acute care surgery
JID - 101570622
RN  - 0 (Reactive Oxygen Species)
RN  - EC 3.1.1.4 (Group VI Phospholipases A2)
RN  - EC 3.1.1.4 (PLA2G6 protein, human)
RN  - EC 3.1.1.4 (Phospholipases A2)
RN  - EC 3.1.1.4 (Phospholipases A2, Cytosolic)
RN  - EC 3.4.21.36 (Pancreatic Elastase)
SB  - IM
MH  - Cells, Cultured
MH  - Chemotaxis/immunology
MH  - Cytotoxicity, Immunologic/*immunology
MH  - Group VI Phospholipases A2/antagonists & inhibitors/*immunology
MH  - Humans
MH  - Intracellular Space/immunology
MH  - Neutrophils/*immunology
MH  - Pancreatic Elastase/metabolism
MH  - Phospholipases A2/*immunology
MH  - Phospholipases A2, Cytosolic/antagonists & inhibitors/metabolism
MH  - Reactive Oxygen Species/metabolism
MH  - Signal Transduction
EDAT- 2015/07/29 06:00
MHDA- 2015/10/08 06:00
CRDT- 2015/07/29 06:00
PHST- 2015/07/29 06:00 [entrez]
PHST- 2015/07/29 06:00 [pubmed]
PHST- 2015/10/08 06:00 [medline]
AID - 01586154-201508000-00010 [pii]
AID - 10.1097/TA.0000000000000730 [doi]
PST - ppublish
SO  - J Trauma Acute Care Surg. 2015 Aug;79(2):238-46. doi: 
      10.1097/TA.0000000000000730.