Pantethine Alters Lipid Composition and Cholesterol Content of Membrane Rafts, With Down‐Regulation of CXCL12‐Induced T Cell Migration

Abstract

Pantethine, a natural low-molecular-weight thiol, shows a broad activity in a large range of essential cellular pathways. It has been long known as a hypolipidemic and hypocholesterolemic agent. We have recently shown that it exerts a neuroprotective action in mouse models of cerebral malaria and Parkinson's disease through multiple mechanisms. In the present study, we looked at its effects on membrane lipid rafts that serve as platforms for molecules engaged in cell activity, therefore providing a target against inappropriate cell response leading to a chronic inflammation. We found that pantethine-treated cells showed a significant change in raft fatty acid composition and cholesterol content, with ultimate downregulation of cell adhesion, CXCL12-driven chemotaxis, and transendothelial migration of various T cell types, including human Jurkat cell line and circulating effector T cells. The mechanisms involved include the alteration of the following: (i) CXCL12 binding to its target cells; (ii) membrane dynamics of CXCR4 and CXCR7, the two CXCL12 receptors; and (iii) cell redox status, a crucial determinant in the regulation of the chemokine system. In addition, we considered the linker for activation of T cells molecule to show that pantethine effects were associated with the displacement from the rafts of the acylated signaling molecules which had their palmitoylation level reduced.. In conclusion, the results presented here, together with previously published findings, indicate that due to its pleiotropic action, pantethine can downregulate the multifaceted process leading to pathogenic T cell activation and migration.

Long-Term Pantethine Treatment Counteracts Pathologic Gene Dysregulation and Decreases Alzheimer's Disease Pathogenesis in a Transgenic Mouse Model

“…At least part of the mechanism leading to Il-1 expression requires the translocation of NF-B to the nucleus that can be achieved after binding of A 42 to TLR2. Although the mechanism of action of pantethine is not yet elucidated, it was shown that pantethine alters lipid composition and cholesterol content of membrane rafts (96). Such an alteration with methyl--cyclodextrin was reported to decrease the levels of nuclear translocation of NF-B p65, phosphorylated ERK1/2 and TLR4 (97, 98).…”

Effect of Pantethine on Ovarian Tumor Progression and Choline Metabolism

“…It was recently shown that pantethine affects lipid raft composition causing a decline of the proportion of saturated fatty acid, an increase in mono- and polyunsaturated fatty acid, and a decrease of cholesterol content (17). These changes in raft composition led to an impairment of CXCL12 to bind to its target (17).…”

“…These changes in raft composition led to an impairment of CXCL12 to bind to its target (17). The CXCL12–CXCR4 axis promotes proliferation, migration, invasion, and metastasis in ovarian cancer (37), therefore its alteration by pantethine may be a mechanism for the reduction of metastases observed in our study.…”

“…TNF-α has been linked to multiple steps of tumorigenesis, including cellular transformation, promotion, survival, proliferation, invasion, angiogenesis, and metastasis (16). Pantethine has also been shown to inhibit CXCL12/CXCR4-induced cell transendothelial migration (17). With its anti-inflammatory and hypolipidemic properties, pantethine appeared to be a good novel candidate against ovarian cancer progression, metastases, and ascites formation.…”

Vitamin B5 and N-Acetylcysteine in Nonalcoholic Steatohepatitis: A Preclinical Study in a Dietary Mouse Model

“…Unlike pantothenate, pantothine may stimulate CoA biosynthesis via PANK-independent mechanisms (51). In addition, pantethine may be able to modulate inflammation and oxidative stress independently of its effects on CoA synthesis (52). …”