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Antiinflammatory properties of a peptide derived from interleukin-4

Klementiev, Boris; Enevoldsen, Maj N.; Li, Shizhong; Carlsson, Robert LU ; Liu, Yawei; Issazadeh-Navikas, Shohreh; Bock, Elisabeth and Berezin, Vladimir (2013) In Cytokine 64(1). p.112-121
Abstract

Interleukin-4 (IL-4) is a potent antiinflammatory cytokine. However its use in the clinic is hampered by side effects. We here describe the identification of a novel synthetic peptide, termed Ph8, derived from α-helix C of IL-4, which interacts with IL-4 receptor α (IL-4Rα). Employing various cultured genetically engineered cell lines and primary lymphocytes, surface plasmon resonance, qPCR, ELISA and immunoblotting techniques we found that Ph8 bound IL-4Rα and mimicked the anti-inflammatory effects of IL-4 by inhibiting TNF-α production by macrophages in vitro. It induced phosphorylation of STAT6 65. kD but inhibited phosphorylation of STAT6 110. kD induced by IL-4 in a B-cell line that expressed the type I receptor. It also inhibited... (More)

Interleukin-4 (IL-4) is a potent antiinflammatory cytokine. However its use in the clinic is hampered by side effects. We here describe the identification of a novel synthetic peptide, termed Ph8, derived from α-helix C of IL-4, which interacts with IL-4 receptor α (IL-4Rα). Employing various cultured genetically engineered cell lines and primary lymphocytes, surface plasmon resonance, qPCR, ELISA and immunoblotting techniques we found that Ph8 bound IL-4Rα and mimicked the anti-inflammatory effects of IL-4 by inhibiting TNF-α production by macrophages in vitro. It induced phosphorylation of STAT6 65. kD but inhibited phosphorylation of STAT6 110. kD induced by IL-4 in a B-cell line that expressed the type I receptor. It also inhibited the IL-4-stimulated expression of a STAT6-inducible reporter gene in cells that expressed the type II receptor. Ph8 inhibited the proliferation of Th1/2 cells and downregulated the production of IFN-γ in stimulated Th1 cells. Moreover, Ph8 did not induce any shift in Th1/Th2 profile. This is a favorable effect and it is indicating that Ph8 could block general T cell activation and inflammatory responses without further inducing the side effects generally associated with IL-4 signaling. These data collectively show that Ph8 is only a partial agonist of IL-4 mimicking its desirable properties. In agreement, Ph8 treatment of rats with collagen-induced arthritis, a Th1- and antibody- mediated disease of joint, delayed the manifestation of chronic inflammation and reduced acute inflammation in carrageenan-induced edema. Our findings indicate that Ph8 is a promising potential drug candidate for the treatment of inflammatory diseases.

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author
publishing date
type
Contribution to journal
publication status
published
keywords
Collagen-induced arthritis, Interferon-γ, Interleukin-4, Signalling, Tumor necrosis factor-α
in
Cytokine
volume
64
issue
1
pages
10 pages
publisher
Academic Press
external identifiers
  • scopus:84883519704
ISSN
1043-4666
DOI
10.1016/j.cyto.2013.07.016
language
English
LU publication?
no
id
267753aa-8b6f-4074-b147-35bb87f25251
date added to LUP
2019-07-02 10:06:50
date last changed
2019-07-03 01:55:33
@article{267753aa-8b6f-4074-b147-35bb87f25251,
  abstract     = {<p>Interleukin-4 (IL-4) is a potent antiinflammatory cytokine. However its use in the clinic is hampered by side effects. We here describe the identification of a novel synthetic peptide, termed Ph8, derived from α-helix C of IL-4, which interacts with IL-4 receptor α (IL-4Rα). Employing various cultured genetically engineered cell lines and primary lymphocytes, surface plasmon resonance, qPCR, ELISA and immunoblotting techniques we found that Ph8 bound IL-4Rα and mimicked the anti-inflammatory effects of IL-4 by inhibiting TNF-α production by macrophages in vitro. It induced phosphorylation of STAT6 65. kD but inhibited phosphorylation of STAT6 110. kD induced by IL-4 in a B-cell line that expressed the type I receptor. It also inhibited the IL-4-stimulated expression of a STAT6-inducible reporter gene in cells that expressed the type II receptor. Ph8 inhibited the proliferation of Th1/2 cells and downregulated the production of IFN-γ in stimulated Th1 cells. Moreover, Ph8 did not induce any shift in Th1/Th2 profile. This is a favorable effect and it is indicating that Ph8 could block general T cell activation and inflammatory responses without further inducing the side effects generally associated with IL-4 signaling. These data collectively show that Ph8 is only a partial agonist of IL-4 mimicking its desirable properties. In agreement, Ph8 treatment of rats with collagen-induced arthritis, a Th1- and antibody- mediated disease of joint, delayed the manifestation of chronic inflammation and reduced acute inflammation in carrageenan-induced edema. Our findings indicate that Ph8 is a promising potential drug candidate for the treatment of inflammatory diseases.</p>},
  author       = {Klementiev, Boris and Enevoldsen, Maj N. and Li, Shizhong and Carlsson, Robert and Liu, Yawei and Issazadeh-Navikas, Shohreh and Bock, Elisabeth and Berezin, Vladimir},
  issn         = {1043-4666},
  keyword      = {Collagen-induced arthritis,Interferon-γ,Interleukin-4,Signalling,Tumor necrosis factor-α},
  language     = {eng},
  month        = {10},
  number       = {1},
  pages        = {112--121},
  publisher    = {Academic Press},
  series       = {Cytokine},
  title        = {Antiinflammatory properties of a peptide derived from interleukin-4},
  url          = {http://dx.doi.org/10.1016/j.cyto.2013.07.016},
  volume       = {64},
  year         = {2013},
}