PKC412 (CGP41251) modulates the proliferation and lipopolysaccharide-induced inflammatory responses of RAW 264.7 macrophages

Journal Article · Fri Aug 17 00:00:00 EDT 2007 · Biochemical and Biophysical Research Communications

DOI:https://doi.org/10.1016/j.bbrc.2007.06.009· OSTI ID:20991495

Miyatake, Katsutoshi ^[1]; Inoue, Hiroshi ^[2]; Hashimoto, Kahoko ^[3]; Takaku, Hiroshi ^[3]; Takata, Yoichiro ^[1]; Nakano, Shunji ^[1]; Yasui, Natsuo ^[1]; Itakura, Mitsuo ^[2]

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1. Department of Orthopedics, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima (Japan)
2. Institute for Genome Research, The University of Tokushima, Tokushima (Japan)
3. Department of Life and Environmental Sciences, Faculty of Engineering, Chiba Institute of Technology, Chiba (Japan)

PKC412 (CGP41251) is a multitarget protein kinase inhibitor with anti-tumor activities. Here, we investigated the effects of PKC412 on macrophages. PKC412 inhibited the proliferation of murine RAW 264.7 macrophages through induction of G2/M cell cycle arrest and apoptosis. At non-toxic drug concentrations, PKC412 significantly suppressed the lipopolysaccharide (LPS)-induced release of TNF-{alpha} and nitric oxide, while instead enhancing IL-6 secretion. PKC412 attenuated LPS-induced phosphorylations of MKK4 and JNK, as well as AP-1 DNA binding activities. Furthermore, PKC412 suppressed LPS-induced Akt and GSK-3{beta} phosphorylations. These results suggest that the anti-proliferative and immunomodulatory effects of PKC412 are, at least in part, mediated through its interference with the MKK4/JNK/AP-1 and/or Akt/GSK-3{beta} pathways. Since macrophages contribute significantly to the development of both acute and chronic inflammation, PKC412 may have therapeutic potential and applications in treating inflammatory and/or autoimmune diseases.

• OSTI ID: 20991495
• Journal Information: Biochemical and Biophysical Research Communications, Vol. 360, Issue 1; Other Information: DOI: 10.1016/j.bbrc.2007.06.009; PII: S0006-291X(07)01229-6; Copyright (c) 2007 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA); ISSN 0006-291X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
APOPTOSIS
CELL CYCLE
CELL PROLIFERATION
DNA
DRUGS
INFLAMMATION
MACROPHAGES
NEOPLASMS
NITRIC OXIDE
PHOSPHORYLATION
PROTEINS
SECRETION
TOXICITY