RESUMO
We have previously shown that naturally occurring as well as acquired Abs against the Mycobacterium tuberculosis heat shock protein (HSP)65 protect against the induction of murine autoimmune inflammatory arthritis. In the present work, we have studied the anti-inflammatory effect of prozumab, a humanized anti-HSP mAb in murine inflammatory arthritis and colitis, and its effects on cytokine secretion. Prozumab was shown to bind to HSP60, the highly conserved mammalian homolog of the bacterial protein, and it was found to be effective in protecting and suppressing autoimmune arthritis in the models of adjuvant arthritis and collagen-induced arthritis in rats and mice, respectively, as well as in acute hapten-mediated colitis and chronic, spontaneous colitis models. Mechanistically, prozumab induces IL-10 secretion from naive human PBMCs and suppresses the secretion of IFN-γ and IL-6 from anti-CD3-activated human PBMCs. These findings make prozumab a promising potential drug for treating human rheumatoid arthritis and inflammatory bowel disease, as well as a wide range of autoimmune inflammatory diseases.
Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Artrite Experimental/tratamento farmacológico , Chaperonina 60/antagonistas & inibidores , Doenças Inflamatórias Intestinais/tratamento farmacológico , Animais , Proteínas de Bactérias/imunologia , Linhagem Celular Tumoral , Chaperonina 60/imunologia , Feminino , Humanos , Interferon gama/metabolismo , Interleucina-10/biossíntese , Interleucina-10/genética , Interleucina-10/metabolismo , Interleucina-6/metabolismo , Células Jurkat , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos DBA , Ligação Proteica/imunologia , Ratos , Ratos Endogâmicos LewRESUMO
Two 3-aminoalkenylphosphonate compounds 1, 2, and a hydroxyl derivative, 2-(3-hydroxy-3-phenylpropyl)hex-1-enylphosphonate 3, recently synthesized in our lab, have been evaluated for their ability to modulate the production of reactive oxygen intermediates, nitric oxide (NO) and tumor necrosis factor (TNF-alpha) by murine macrophages. We found that all three molecules suppressed generation of reactive oxygen intermediates, NO, and TNF-alpha. However, although 2-(3-hydroxy-3-phenylpropyl)hex-1-enylphosphonate 3 possessed higher activity in suppression of reactive oxygen intermediates and nitric oxide compared to 3-aminoalkenylphosphonates 1 and 2, it showed less activity in the inhibition of tumor necrosis factor release.
Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Macrófagos Peritoneais/efeitos dos fármacos , Óxido Nítrico/antagonistas & inibidores , Organofosfonatos/farmacologia , Espécies Reativas de Oxigênio/antagonistas & inibidores , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Compostos de Vinila/farmacologia , Animais , Linhagem Celular , Feminino , Macrófagos Peritoneais/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Óxido Nítrico/biossíntese , Espécies Reativas de Oxigênio/metabolismo , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Cannabidiol (CBD) and cannabidiol dimethyl hephtyl (CBD-DMH) were hydrogenated to give four different epimers. The new derivatives were evaluated for their ability to modulate the production of reactive oxygen intermediates (ROI), nitric oxide (NO), and tumor necrosis factor (TNF-alpha) by murine macrophages, and for their binding to the cannabinoid receptor (CB(1)). Surprisingly, we found that these derivatives exhibit good binding to CB(1). In addition hydrogenated CBD and CBD-DMH demonstrate bioactivities different from their original compounds.
Assuntos
Anti-Inflamatórios não Esteroides/síntese química , Canabidiol/análogos & derivados , Canabidiol/síntese química , Receptor CB1 de Canabinoide/metabolismo , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Tronco Encefálico/efeitos dos fármacos , Tronco Encefálico/metabolismo , Canabidiol/farmacologia , Linhagem Celular , Técnicas In Vitro , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Óxido Nítrico/biossíntese , Ensaio Radioligante , Ratos , Espécies Reativas de Oxigênio/metabolismo , Relação Estrutura-Atividade , Sinaptossomos/efeitos dos fármacos , Sinaptossomos/metabolismo , Fator de Necrose Tumoral alfa/biossínteseRESUMO
Two non-psychotropic cannabinoids, cannabidiol (CBD) and cannabidiol-dimethylheptyl (CBD-DMH), induced apoptosis in a human acute myeloid leukemia (AML) HL-60 cell line. Apoptosis was determined by staining with bisBenzimide and propidium iodide. A dose dependent increase of apoptosis was noted, reaching 61 and 43% with 8 microg/ml CBD and 15 microg/ml CBD-DMH, respectively, after a 24 h treatment. Prior exposure of the cells to gamma-irradiation (800 cGy) markedly enhanced apoptosis, reaching values of 93 and 95%, respectively. Human monocytes from normal individuals were resistant to either cannabinoids or gamma-irradiation. Caspase-3 activation was observed after the cannabinoid treatment, and may represent a mechanism for the apoptosis. Our data suggest a possible new approach to treatment of AML.
Assuntos
Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Canabidiol/análogos & derivados , Canabidiol/farmacologia , Ativação Enzimática/efeitos dos fármacos , Ativação Enzimática/efeitos da radiação , Caspase 3 , Caspases/metabolismo , Raios gama , Células HL-60/efeitos dos fármacos , Células HL-60/efeitos da radiação , Humanos , Monócitos/efeitos dos fármacos , Monócitos/efeitos da radiaçãoRESUMO
We have previously shown that intravenous (i.v.) treatment with sterically stabilized nano-liposomes (NSSL) actively remote-loaded with the glucocorticoid (GC) methylprednisolone hemisuccinate (NSSL-MPS) or betamethasone hemisuccinate (NSSL-BMS) significantly decreased severity of adjuvant arthritis in Lewis rats (a model of human rheumatoid arthritis) throughout all disease stages. Here, we compared i.v. or subcutaneous (s.c.) weekly treatment with each of the two NSSL-GC to weekly or daily treatment with the free drugs or with the TNF-α antagonists Infliximab and Etanercept. Therapeutic efficacy and effects on the profile of pro-inflammatory (IL-6, TNF-α, and INF-γ) and anti-inflammatory (IL-10 and TGF-ß) cytokines in rat sera and splenocyte tissue culture supernatants were compared to those of the liposomal and free drugs. Both s.c. and i.v. NSSL-GC suppressed arthritis significantly, compared to higher doses of the free drugs or to TNF-α antagonists. NSSL-GC also suppressed the secretion of pro-inflammatory cytokines, but did not change the levels of TGF- ß. The highly efficacious anti-inflammatory therapeutic feature of these nano-drugs makes them candidates for treatment of human rheumatoid arthritis.