Antiinflammatory properties of a peptide derived from interleukin-4

Boris Klementiev; Maj N Enevoldsen; Shizhong Li; Robert Carlsson; Yawei Liu; Shohreh Navikas; Elisabeth Bock; Vladimir Berezin

doi:10.1016/j.cyto.2013.07.016

Antiinflammatory properties of a peptide derived from interleukin-4

Boris Klementiev, Maj N Enevoldsen, Shizhong Li, Robert Carlsson, Yawei Liu, Shohreh Navikas, Elisabeth Bock, Vladimir Berezin

Cell and Neurobiology

4 Citations (Scopus)

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 65kD 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.

Original language	English
Journal	Cytokine
Volume	64
Issue number	1
Pages (from-to)	112-21
Number of pages	10
ISSN	1043-4666
DOIs	https://doi.org/10.1016/j.cyto.2013.07.016
Publication status	Published - Oct 2013

Keywords

Animals
Anti-Inflammatory Agents, Non-Steroidal
Arthritis, Experimental
Cell Proliferation
Edema
HEK293 Cells
Humans
Interferon-gamma
Interleukin-4
Interleukin-4 Receptor alpha Subunit
Lymphocyte Activation
Macrophage Activation
Macrophages
Male
Mice
Mice, Inbred C57BL
Peptide Fragments
Phosphorylation
Protein Binding
Rats
Rats, Wistar
STAT6 Transcription Factor
Th1 Cells
Tumor Necrosis Factor-alpha

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10.1016/j.cyto.2013.07.016

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title = "Antiinflammatory properties of a peptide derived from interleukin-4",

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 65kD 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.",

keywords = "Animals, Anti-Inflammatory Agents, Non-Steroidal, Arthritis, Experimental, Cell Proliferation, Edema, HEK293 Cells, Humans, Interferon-gamma, Interleukin-4, Interleukin-4 Receptor alpha Subunit, Lymphocyte Activation, Macrophage Activation, Macrophages, Male, Mice, Mice, Inbred C57BL, Peptide Fragments, Phosphorylation, Protein Binding, Rats, Rats, Wistar, STAT6 Transcription Factor, Th1 Cells, Tumor Necrosis Factor-alpha",

author = "Boris Klementiev and Enevoldsen, {Maj N} and Shizhong Li and Robert Carlsson and Yawei Liu and Shohreh Navikas and Elisabeth Bock and Vladimir Berezin",

year = "2013",

month = oct,

doi = "10.1016/j.cyto.2013.07.016",

language = "English",

volume = "64",

pages = "112--21",

journal = "Cytokine",

issn = "1043-4666",

publisher = "Academic Press",

number = "1",

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T1 - Antiinflammatory properties of a peptide derived from interleukin-4

AU - Klementiev, Boris

AU - Enevoldsen, Maj N

AU - Li, Shizhong

AU - Carlsson, Robert

AU - Liu, Yawei

AU - Navikas, Shohreh

AU - Bock, Elisabeth

AU - Berezin, Vladimir

PY - 2013/10

Y1 - 2013/10

N2 - 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 65kD 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.

AB - 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 65kD 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.

KW - Animals

KW - Anti-Inflammatory Agents, Non-Steroidal

KW - Arthritis, Experimental

KW - Cell Proliferation

KW - Edema

KW - HEK293 Cells

KW - Humans

KW - Interferon-gamma

KW - Interleukin-4

KW - Interleukin-4 Receptor alpha Subunit

KW - Lymphocyte Activation

KW - Macrophage Activation

KW - Macrophages

KW - Male

KW - Mice

KW - Mice, Inbred C57BL

KW - Peptide Fragments

KW - Phosphorylation

KW - Protein Binding

KW - Rats

KW - Rats, Wistar

KW - STAT6 Transcription Factor

KW - Th1 Cells

KW - Tumor Necrosis Factor-alpha

U2 - 10.1016/j.cyto.2013.07.016

DO - 10.1016/j.cyto.2013.07.016

M3 - Journal article

C2 - 23972727

SN - 1043-4666

VL - 64

SP - 112

EP - 121

JO - Cytokine

JF - Cytokine

IS - 1

ER -

Antiinflammatory properties of a peptide derived from interleukin-4

Abstract

Keywords

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