Composition for treating sepsis or septic shock comprising the peptide originated from the smad6

Abstract

Disclosed is a pharmaceutical composition comprising a Smad6-derived peptide as an active ingredient. Having ability to specifically bind to Pellino-1, the Smad6-derived peptide is effectively useful in the treatment of the sepsis mediated by excessively activated TLR. The peptide effectively reduces the expression of inflammatory cytokines, protects cells from sepsis-induced apoptosis, and exhibits high bacterial clearance in animal models of sepsis.

What is claimed is: 
     
         1 . A pharmaceutical composition for treatment of sepsis or septic shock, comprising a Smad6-derived peptide consisting of the amino acid sequence represented by SEQ ID NO: 1, as an active ingredient. 
     
     
         2 . The pharmaceutical composition of  claim 1 , wherein the sepsis is characterized by activation of Toll-like receptor 4 (TLR4). 
     
     
         3 . The pharmaceutical composition of  claim 1 , wherein the Smad6-derived peptide exerts a therapeutic effect on sepsis by inhibiting production of inflammatory cytokines IL-6, TNF-α, IFN-γ and IL-1β, activity of caspase-3, or proliferation of TUNEL-positive cells. 
     
     
         4 . The pharmaceutical composition of  claim 1 , wherein the Smad6-derived peptide upregulates expression of a chemokine receptor CXCR2 by inhibiting the expression of GRK2 that is inhibitory of expression of the chemokine receptor CXCR2. 
     
     
         5 . The pharmaceutical composition of  claim 1 , wherein the Smad6-derived peptide downregulates an IFN-1β-TRAIL pathway by inhibiting formation of an IKKε/TBK1/Pellino-1 complex. 
     
     
         6 . The pharmaceutical composition of  claim 1 , wherein the Smad6-derived peptide binds to Pellino-1. 
     
     
         7 . A method for treatment of sepsis or septic shock, comprising administering a pharmaceutical composition in a pharmaceutically effective amount to a subject in need thereof, said pharmaceutical composition comprising a Smad6-derived peptide consisting of the amino acid sequence of SEQ ID NO: 1, as an active ingredient. 
     
     
         8 . The method of  claim 7 , wherein the sepsis is mediated by activation of Toll-like receptor 4 (TLR4). 
     
     
         9 . The method of  claim 7 , wherein the effective amount of the Smad6-derived peptide is an amount effective to exert a therapeutic effect on sepsis by inhibiting production of inflammatory cytokines IL-6, TNF-α, IFN-γ and IL-1β, activity of caspase-3, or proliferation of TUNEL-positive cells. 
     
     
         10 . The method of  claim 7 , wherein the effective amount of the Smad6-derived peptide is an amount effective to upregulate expression of a chemokine receptor CXCR2 by inhibiting the expression of GRK2 that is inhibitory of expression of the chemokine receptor CXCR2. 
     
     
         11 . The method of  claim 7 , wherein the effective amount of the Smad6-derived peptide is an amount effective to downregulate an IFN-β1-TRAIL pathway by inhibiting formation of an IKKε/TBK1/Pellino-1 complex. 
     
     
         12 . The method of  claim 7 , wherein the effective amount of the Smad6-derived peptide is an amount effective to bind to Pellino-1. 
     
     
         13 . The method of  claim 7 , wherein the administering occurs within 10 hours of the onset of sepsis or septic shock. 
     
     
         14 . The method of  claim 13 , wherein the administering occurs within 4 hours of the onset of sepsis or septic shock. 
     
     
         15 . The method of  claim 14 , wherein the administering occurs within 2 hours of the onset of sepsis or septic shock. 
     
     
         16 . The method of  claim 7 , wherein the administering comprises an initial administration followed by a subsequent administration about 12 hours after the initial administration.