Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 5 de 5
Filter
Add more filters










Database
Language
Publication year range
1.
Peptides ; 32(8): 1567-74, 2011 Aug.
Article in English | MEDLINE | ID: mdl-21723351

ABSTRACT

A potential link between obesity, circulating leptin levels and autoimmune disease symptoms suggests that targeting the leptin receptor (ObR) might be a viable novel strategy to combat rheumatoid arthritis (RA). However, studies in animal models and evaluation of clinical cases did not provide clear view on leptin's involvement in RA. To validate ObR as RA target, we used our peptide-based ObR agonists and antagonist in different in vitro and in vivo models of the disease. In human peripheral blood mononuclear cells, leptin and its agonist fragment, desI(2)-E1/Aca, moderately induced constitutive activation of a major proinflammatory transcription factor, NF-κB, while the ObR antagonist peptide Allo-aca inhibited the process. Leptin administration itself did not induce arthritis in rats, but worsened the clinical condition of mice given K/BxN serum transfer arthritis. Simultaneous administration of Allo-aca reduced leptin-dependent increase in disease severity by more than 50%, but the antagonist was ineffective when injected with a 3-day delay. In rats inflicted with mild adjuvant-induced arthritis, both leptin and Allo-aca reduced the extent of joint swelling and the number of arthritic joints. In a more aggressive disease stage, Allo-aca decreased the number of arthritic joints in a dose-dependent manner but did not affect other arthritis markers. In summary, leptin exerts diverse effects on RA depending on the experimental model. This might reflect the heterogeneous character of RA, which is differently impacted by leptin and is unmasked by ObR antagonism. Nevertheless, the results suggest that ObR antagonists might become useful therapeutics in leptin-sensitive early stages of RA.


Subject(s)
Arthritis, Rheumatoid/metabolism , Leptin/metabolism , Receptors, Leptin/antagonists & inhibitors , Animals , Arthritis, Experimental/metabolism , Disease Models, Animal , Female , Humans , Leukocytes, Mononuclear/metabolism , Mice , Mice, Transgenic , Oligopeptides/pharmacology , Rats , Receptors, Leptin/metabolism
2.
J Pept Sci ; 14(6): 714-24, 2008 Jun.
Article in English | MEDLINE | ID: mdl-18240131

ABSTRACT

Core peptide (CP; GLRILLLKV) is a 9-amino acid peptide derived from the transmembrane sequence of the T-cell antigen receptor (TCR) alpha-subunit. CP inhibits T-cell activation both in vitro and in vivo by disruption of the TCR at the membrane level. To elucidate CP interactions with lipids, surface plasmon resonance (SPR) and circular dichroism (CD) were used to examine CP binding and secondary structure in the presence of either the anionic dimyristoyl-L-alpha-phosphatidyl-DL-glycerol (DMPG), or the zwitterionic dimyristoyl-L-alpha-phoshatidyl choline (DMPC). Using lipid monolayers and bilayers, SPR experiments demonstrated that irreversible peptide-lipid binding required the hydrophobic interior provided by a membrane bilayer. The importance of electrostatic interactions between CP and phospholipids was highlighted on lipid monolayers as CP bound reversibly to anionic DMPG monolayers, with no detectable binding observed on neutral DMPC monolayers.CD revealed a dose-dependent conformational change of CP from a dominantly random coil structure to that of beta-structure as the concentration of lipid increased relative to CP. This occurred only in the presence of the anionic DMPG at a lipid : peptide molar ratio of 1.6:1 as no conformational change was observed when the zwitterionic DMPC was tested up to a lipid : peptide ratio of 8.4 : 1.


Subject(s)
Membranes, Artificial , Peptides/chemistry , Receptors, Antigen, T-Cell/chemistry , Kinetics , Protein Conformation , Protein Structure, Secondary , Surface Plasmon Resonance
3.
Mol Immunol ; 45(4): 876-80, 2008 Feb.
Article in English | MEDLINE | ID: mdl-17915329

ABSTRACT

Antigenic peptides initiate an immune response in T cells via the T cell receptor (TCR). The TCR itself is widely regarded as one of the most complex receptors in nature, as it is comprised of at least six different subunits, the antigen recognizing TCRalpha and beta chains, and the signal transmitting CD3deltavarepsilon, gammaepsilon, and zeta2 dimers. In order for a signal to be transmitted from the TCR to the cytoplasm, the CD3 chains must "sense" that an antigenic peptide has been presented to the TCRalpha and beta subunits. After accomplishing this, there are a total of 10 different immunoreceptor tyrosine activation motifs (ITAMs) present within the CD3 chains which effectively activate the T cell and hence the immune response. The importance of each CD3 chain and subsequently each ITAM has been the focus of intense research. However, the precise role(s) played by each CD3 chain has remained elusive. Using the immunomodulatory peptide termed core peptide (CP), which is proposed to inhibit TCR activation by disrupting TCR-CD3 interactions, a tri-modular signaling system for T cell activation is proposed. By contrast to the existing two distinct signaling model (zeta2, CD3epsilongamma/epsilondelta), in this model each of the three dimers, CD3gammaepsilon, deltaepsilon, and zeta2, are proposed to act as three separate and distinct signaling modules, performing both specific and redundant functions.


Subject(s)
CD3 Complex/immunology , Models, Immunological , Receptors, Antigen, T-Cell/physiology , T-Lymphocytes/immunology , Animals , Dimerization , Humans , Immunity, Cellular , Lymphocyte Activation , Protein Subunits/physiology , Receptor-CD3 Complex, Antigen, T-Cell/physiology , Signal Transduction
4.
Biochim Biophys Acta ; 1763(8): 879-88, 2006 Aug.
Article in English | MEDLINE | ID: mdl-16782215

ABSTRACT

A T cell antigen receptor (TCR) transmembrane sequence derived peptide (CP) has been shown to inhibit T cell activation both in vitro and in vivo at the membrane level of the receptor signal transduction. To examine the effect of sugar or lipid conjugations on CP function, we linked CP to 1-aminoglucosesuccinate (GS), N-myristate (MYR), mono-di-tripalmitate (LP1, LP2, or LP3), and a lipoamino acid (LA) and examined the effects of these compounds on T cell activation in vitro and by using a rat model of adjuvant-induced arthritis, in vivo. In vitro, antigen presentation results demonstrated that lipid conjugation enhanced CP's ability to lower IL-2 production from 56.99%+/-15.69 S.D. observed with CP, to 12.08%+/-3.34 S.D. observed with LA. The sugar conjugate GS resulted in only a mild loss of in vitro activity compared to CP (82.95%+/-14.96 S.D.). In vivo, lipid conjugation retarded the progression of adjuvant-induced arthritis by approximately 50%, whereas the sugar conjugated CP, GS, almost completely inhibited the progression of arthritis. This study demonstrates that hydrophobic peptide activity is markedly enhanced in vitro and in vivo by conjugation to lipids or sugars. This may have practical applications in drug delivery and bioavailability of hydrophobic peptides.


Subject(s)
Peptide Fragments/chemistry , Peptide Fragments/metabolism , Receptors, Antigen, T-Cell, alpha-beta/chemistry , Receptors, Antigen, T-Cell, alpha-beta/metabolism , Amino Acid Sequence , Animals , Antigen Presentation , Arthritis, Experimental/drug therapy , Arthritis, Experimental/etiology , Arthritis, Experimental/immunology , CD3 Complex/metabolism , Cell Line , Cell Proliferation/drug effects , Cell Survival/drug effects , Cross-Linking Reagents/pharmacology , Enterotoxins/pharmacology , Female , Glycosylation , Hydrophobic and Hydrophilic Interactions , In Vitro Techniques , Interleukin-2/biosynthesis , Ionomycin/pharmacology , Lipids/chemistry , Lymphocyte Activation/drug effects , Mice , Peptide Fragments/genetics , Peptide Fragments/pharmacology , Rats , Rats, Wistar , Receptors, Antigen, T-Cell, alpha-beta/genetics , T-Lymphocytes/drug effects , T-Lymphocytes/immunology , Tetradecanoylphorbol Acetate/pharmacology
5.
Can J Urol ; 6(5): 853-858, 1999 Oct.
Article in English | MEDLINE | ID: mdl-11180782

ABSTRACT

OBJECTIVES: Microsatellite instability has been found in a variety of tumors including prostate cancer. Bax, a pro-apoptotic protein from the Bcl-2 family of proteins, has a microsatellite composed of an eight deoxyguanine [(G)8] tract located in exon 3. Prostate carcinoma cells have increased proliferation indices and lower levels of apoptosis when compared to benign tissue. We investigated whether instability in the Bax (G)8 microsatellite contributes to loss of apoptotic control in localized prostate cancer. PATIENTS AND METHODS: Thirty-eight patients undergoing radical prostatectomy for localized prostate carcinoma participated in this study. Prostate carcinoma was microdissected, and polymerase chain reaction amplification of a region containing the (G)8 microsatellite was performed on DNA from peripheral blood leukocytes and tumors, followed by single strand conformational polymorphism (SSCP) analysis and direct DNA sequencing. RESULTS: SSCP analysis showed no alteration in the number of bands detected upon comparison of tumor tissue to leukocytes, suggesting no alterations in the microsatellite. This was confirmed by direct sequencing, which demonstrated a normal (G)8 sequence in each case. CONCLUSION: We conclude that the Bax (G)8 microsatellite is stable in localized stage T2 and T3 prostate cancer. Our findings argue against a mutator phenotype pathway leading to loss of apoptotic control in localized prostate cancer.

SELECTION OF CITATIONS
SEARCH DETAIL
...