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.
authors: Department of Neuroscience and Pharmacology, University of Copenhagen, Copenhagen, Denmark.
authors: Boris
authors: B
authors: Klementiev
authors: Maj N
authors: MN
authors: Enevoldsen
authors: Shizhong
authors: S
authors: Li
authors: Robert
authors: R
authors: Carlsson
authors: Yawei
authors: Y
authors: Liu
authors: Shohreh
authors: S
authors: Issazadeh-Navikas
authors: Elisabeth
authors: E
authors: Bock
authors: Vladimir
authors: V
authors: Berezin
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001169:Arthritis, Experimental / Q000188:drug therapy; D049109:Cell Proliferation / Q000187:drug effects; D004487:Edema / Q000188:drug therapy; D057809:HEK293 Cells; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D015847:Interleukin-4 / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology*; D053662:Interleukin-4 Receptor alpha Subunit / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D008262:Macrophage Activation / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010446:Peptide Fragments / Q000737:chemistry / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding; D051381:Rats; D017208:Rats, Wistar; D050800:STAT6 Transcription Factor / Q000378:metabolism; D018417:Th1 Cells / Q000187:drug effects / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D053662:Interleukin-4 Receptor alpha Subunit; D010446:Peptide Fragments; C587783:Ph8 peptide; D050800:STAT6 Transcription Factor; D014409:Tumor Necrosis Factor-alpha; D015847:Interleukin-4; D007371:Interferon-gamma
keywords: APCs; BrdU; CFA; CIA; CII; Collagen-induced arthritis; DLNs; Dx; HEK; IFN-γ; IL; IL-R; IL-receptor; Interferon-γ; Interleukin-4; JAK; Janus kinase; MOG(35–55); MTX; NF-κB; SEAP; STAT; Signalling; TNF-α; Tumor necrosis factor-α; antigen-presenting cells; bromodeoxyuridine; collagen type II; collagen-induced arthritis; complete Freund’s adjuvant; dexamethasone 21-disodium phosphate; draining lymph nodes; human embryonic kidney; interferon-γ; interleukin; methotrexate; myelin oligodendrocyte glycoprotein 35–55; nuclear factor-κB; secreted embryonic alkaline phosphatase; signal transducer and activator of transcription; tumor necrosis factor α