The OGF–OGFr Axis Utilizes the p16^INK4aand p21^WAF1/CIP1Pathways to Restrict Normal Cell Proliferation

Abstract

Opioid growth factor (OGF) is an endogenous opioid peptide ([Met5

Synergistic effect of methionine encephalin (MENK) combined with pidotimod(PTD) on the maturation of murine dendritic cells (DCs)

“…30 MENK possesses bilateral regulation on immune cells, which means that MENK at higher concentrations such as 10 -6 M or lower concentrations such as 10 -18 M will delay immune cell growth and the possible mechanism is MENK can interact with OGFr to upregulate cyclin-dependent kinase inhibitory (CKI) pathways and markedly delay the G 1 /S phase of the cell cycle. [31][32][33][34] However, MENK at a range of physiological concentrations between 10 -11 and 10 -15 M will enhance immune cell growth. Beyond the wellknown interaction of MENK with the μ-and δ-opioid receptor, the peptide has been shown to bind with a distinct receptor-type, named zeta (ζ) receptors.…”

“…Recently, scientists have identified a novel endogenous opioid system (OGF-OGFr) that inhibited cell proliferation, migration, angiogenesis, and tissue organization. 31,34,[36][37][38][39] Our previous work has proven that MENK could intensify in the DC-CD4+T cell pathway, stimulate proliferation of lymphocytes in human peripheral blood, induce DC progenitors to develop to mDC, and drive macrophage polarization into M1-type in mice bearing tumor. 27,[40][41][42] PTD, a synthetic substance, has been shown to ameliorate different functions of innate and adaptive immune responses both in animals and humans.…”

Featured Article: Nuclear export of opioid growth factor receptor is CRM1 dependent

“…For DNA synthesis studies, cells were pulsed with 30 mM 5-bromo-2 0 -deoxyuridine (BrdU) 3 h prior to fixing, and stained with anti-BrdU (B35132, Invitrogen) as well as anti-GFP (A21311, Invitrogen) following previous protocols. 1,5 Protein detection by Western blotting Cells were trypsinized, collected, and lysed in RIPA buffer plus protease inhibitors (Complete mini EDTA-free, 11836170001) and phosphatase inhibitors (PhosStop, 04906837001). Equal volumes were loaded onto SDS-PAGE gels, electrophoresed at 100 volts, and transferred onto nitrocellulose.…”

“…5 The mechanism of action of the OGF-OGFr axis is related to DNA synthesis, targeting the p16/p21 cyclin-dependent kinase inhibitory pathway and delaying the G1-S phase of the cell cycle. 1,6 OGFr has three nuclear localization signals (NLS), NLS 267-296 , NLS [383][384][385][386] , and NLS 456-460. 7 Two of the three NLSs, NLS [383][384][385][386] , and NLS [456][457][458][459][460] are essential for nuclear localization of the receptor.…”

Targeting opioid signaling in Crohn’s disease: new therapeutic pathways

“…These characteristics are all hallmarks of the OGF-OGFr pathway [7,15,20]. Given that opioid signaling, and in particular OGF, is important to the course of CD as well as other autoimmune diseases (e.g., multiple sclerosis), and that modulation of the OGF-OGFr axis by LDN, as in the case of CD, or by OGF or LDN for experimental autoimmune encephalomyelitis (a model for multiple sclerosis), can attenuate autoimmune diseases, the relationship of OGF to the immune response needs to be addressed.…”