Antisense to protein kinase C-alpha and p47phox attenuates the pro-inflammatory effects of human C-reactive protein in macrophages of biobreeding diabetic rats.
OBJECTIVE
Type 1 diabetes mellitus (T1DM) is a pro-inflammatory state characterized by high C-reactive protein (CRP) levels. Previously, we showed that CRP accentuated a macrophage (MO) activity in spontaneously diabetic biobreeding (BB) rats and increased the MO activity of protein kinase C-alpha (PKC-α) and p47phox. In this report, we tested the effects of molecular inhibition of CRP effects on MO activity using antisense oligonucleotide (ASO) to both PKC-α and p47phox.


METHODS
Prior to administration of human C-reactive protein (hCRP) daily for 3 days, ASO or scrambled ASO to either PKC-α or p47phox was also delivered for 3 days and after killing on day 4, peritoneal MOs were isolated.


RESULTS
The increase in the levels of superoxide anion, interleukin (IL)-1, monocyte chemoattractant protein-1 (MCP-1), tumour necrosis factor-alpha (TNF-α) and IL-6 release in MOs with hCRP compared to human albumin was significantly attenuated by antisense to either PKC-α and p47phox (p < 0.01 vs. scrambled ASO; n = 5 per group).


CONCLUSIONS
Our novel data suggest that antisense to either PKC-α or p47phox attenuates the pro-inflammatory effects of human CRP on MOs in diabetic rats.
Laboratory for Atherosclerosis and Metabolic Research, Department of Pathology and Laboratory Medicine, University of California at Davis, Sacramento, CA 95817, USA. ishwarlal.jialal@ucdmc.ucdavis.edu
Ishwarlal
I
Jialal
Sridevi
S
Devaraj
D000818:Animals; D002097:C-Reactive Protein / Q000008:administration & dosage / Q000378:metabolism*; D018932:Chemokine CCL2 / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000201:enzymology / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D004195:Disease Models, Animal; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D018836:Inflammation Mediators / Q000008:administration & dosage / Q000378:metabolism*; D007274:Injections, Intraperitoneal; D007375:Interleukin-1 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000201:enzymology* / Q000276:immunology; D008297:Male; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism*; D020320:Oligoribonucleotides, Antisense / Q000008:administration & dosage*; D051571:Protein Kinase C-alpha / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D013481:Superoxides / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
C491766:Ccl2 protein, rat; D018932:Chemokine CCL2; D018836:Inflammation Mediators; D007375:Interleukin-1; D015850:Interleukin-6; D020320:Oligoribonucleotides, Antisense; D014409:Tumor Necrosis Factor-alpha; D013481:Superoxides; D002097:C-Reactive Protein; D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1; D051571:Protein Kinase C-alpha