Abstract
PTEN is a tyrosine phosphatase with significant function in inhibiting STAT3 activation. Recently, inactivation of STAT3 has been demonstrated as a therapeutic candidate for autoimmune arthritis. The expression of PTEN controlled by p53 regulates autoimmune arthritis through modulating the balance between Th17 and Treg. We hypothesized that PTEN regulated by p53 might reduce CIA severity and inflammatory response via inhibiting STAT3 activation. Our results revealed that PTEN could ameliorate experimental autoimmune arthritis by reducing STAT3 activity and Th17 differentiation. Systemic infusion of PTEN overexpression downregulated CIA severity. In addition, PTEN overexpression decreased the activation of T cells and modulated reciprocal differentiation of Th17 and Treg cells. We observed that PTEN expression downregulated by p53 deficiency induced the activation of STAT3. Loss of p53 exacerbated autoimmune arthritis and dysregulated the population of Th17 and Treg. These data suggest that induction of STAT3-modulatory activity of PTEN may be a therapeutic target for rheumatoid arthritis therapy.
Highlights
Rheumatoid arthritis (RA) is a complex autoimmune disorder that induces chronic inflammatory response
The concentrations of total IgG, IgG1, and IgG2a in the serum were significantly decreased in mice injected with Phosphatase and tensin homolog (PTEN) overexpression compared to mock group (Fig. 1B)
Immunohistochemical analysis revealed that injection with PTEN overexpression vector significantly suppressed the expression of proinflammatory cytokines and osteoclastogenesis related factor such as RANKL and TRAP in joints compared to Collagen-induced arthritis (CIA) mice treated with mock vector (Fig. 1D,E)
Summary
Rheumatoid arthritis (RA) is a complex autoimmune disorder that induces chronic inflammatory response. IL-17 expression can lead to chronic immune inflammatory response in patients with RA3. STAT3 plays a key role in immune inflammatory response. It is a potential target for treatment of RA. It has been suggested that STAT3 inhibition can attenuate experimental autoimmune arthritis progression and downregulate Th17 differentiation[9,10]. Phosphatase and tensin homolog (PTEN), a tumor suppressive factor, is a 3′-specific phosphatidylinositol 3,4,5-treiphosphate phosphatase[11] PTEN plays a key role in the development of immune response. PTEN production is associated with tumor protein p53 involving in the reduction of autoimmune inflammatory response[15]. We hypothesized that PTEN could attenuate the development of autoimmune arthritis by reducing STAT3 activation and Th17 cells differentiation. We evaluated the therapeutic efficacy of PTEN in experimental autoimmune arthritis
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