PMID- 1482652
OWN - NLM
STAT- MEDLINE
DCOM- 19930217
LR  - 20190704
IS  - 0007-1048 (Print)
IS  - 0007-1048 (Linking)
VI  - 82
IP  - 4
DP  - 1992 Dec
TI  - Polyethylene glycol (PEG) modification of granulocyte-macrophage colony 
      stimulating factor (GM-CSF) enhances neutrophil priming activity but not colony 
      stimulating activity.
PG  - 654-63
AB  - PEG-modified proteins have numerous advantages over their unmodified counterparts 
      (increased half life, reduced antigenicity, improved solubility), but almost 
      without exception, they show a modest to marked reduction in biological or 
      enzymatic activity. However, while investigating a new protocol for the 
      preparation of PEG-proteins, we compared PEG-modified and unmodified GM-CSF with 
      respect to their polymorphonuclear neutrophil granulocyte (PMN) priming 
      activities. PEG-GM-CSF was unexpectedly more active than GM-CSF in its ability to 
      prime neutrophils to respond to the synthetic peptide 
      n-formyl-methionyl-leucyl-phenylalanine (FMLP) with an oxidative burst (assessed 
      both by nitroblue tetrazolium reduction and ferricytochrome c reduction). These 
      results were in contrast to the findings for colony stimulating activity and with 
      GM-CSF induced thymidine uptake, where the biological activity was unchanged or 
      reduced. The enhanced neutrophil priming activity of PEG-GM-CSF was confirmed 
      using FPLC fractionated PEG-modified GM-CSF. This showed changes in the 
      bioactivity profile consistent with both the shift in protein elution profile and 
      enhanced activity of the PEG-modified material (reflected in the increased area 
      under the bioactivity curve). We also excluded a neutrophil priming action for 
      PEG-modified fetal calf serum proteins, carrier proteins and 'irrelevant' 
      cytokine, erythropoietin. The dissociation of the two bioactivities was confirmed 
      using individual FPLC fractions. These results suggest the presence of 
      differences in either binding, receptor/ligand processing or signal transduction 
      for neutrophils versus progenitors, that are differentially affected by 
      PEG-modification of GM-CSF. The demonstration that PEG-modification can partially 
      dissociate two biological activities suggests the feasibility of using 
      PEG-modification to produce proteins with subtly altered spectra of biological 
      activity and hence new ranges of clinical applications.
FAU - Knusli, C
AU  - Knusli C
AD  - Molecular Cell Pathology Laboratory, Royal Free Hospital School of Medicine, 
      London.
FAU - Delgado, C
AU  - Delgado C
FAU - Malik, F
AU  - Malik F
FAU - Domine, M
AU  - Domine M
FAU - Tejedor, M C
AU  - Tejedor MC
FAU - Irvine, A E
AU  - Irvine AE
FAU - Fisher, D
AU  - Fisher D
FAU - Francis, G E
AU  - Francis GE
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Br J Haematol
JT  - British journal of haematology
JID - 0372544
RN  - 3WJQ0SDW1A (Polyethylene Glycols)
RN  - 59880-97-6 (N-Formylmethionine Leucyl-Phenylalanine)
RN  - 83869-56-1 (Granulocyte-Macrophage Colony-Stimulating Factor)
RN  - VC2W18DGKR (Thymidine)
SB  - IM
MH  - Cells, Cultured
MH  - Dose-Response Relationship, Drug
MH  - Granulocyte-Macrophage Colony-Stimulating Factor/*drug effects/pharmacology
MH  - Hematopoietic Stem Cells/cytology/*drug effects
MH  - Humans
MH  - N-Formylmethionine Leucyl-Phenylalanine/pharmacology
MH  - Neutrophils/*drug effects/metabolism
MH  - Polyethylene Glycols/*pharmacology
MH  - Thymidine/metabolism
EDAT- 1992/12/01 00:00
MHDA- 1992/12/01 00:01
CRDT- 1992/12/01 00:00
PHST- 1992/12/01 00:00 [pubmed]
PHST- 1992/12/01 00:01 [medline]
PHST- 1992/12/01 00:00 [entrez]
AID - 10.1111/j.1365-2141.1992.tb06940.x [doi]
PST - ppublish
SO  - Br J Haematol. 1992 Dec;82(4):654-63. doi: 10.1111/j.1365-2141.1992.tb06940.x.