An Essential Role for RIG-I in Toll-like Receptor-Stimulated Phagocytosis

SummaryRetinoic acid-inducible gene-I (RIG-I) plays an important role in antiviral response by recognizing double-stranded RNA. Here we demonstrate an unanticipated role of RIG-I in Toll-like receptor (TLR)-stimulated phagocytosis. Stimulation with lipopolysaccharide (LPS), a ligand of TLR4, induced the expression of RIG-I in macrophages. Depletion of RIG-I by RNAi or gene targeting inhibited the LPS-induced phagocytosis of bacteria. Cellular processes involved in phagocytosis, such as small GTPase Cdc42/Rac1 activation, actin polymerization, and actin-regulator Arp2/3 recruitment, were also impaired in RIG-I-deficient macrophages activated by LPS. Moreover, RIG-I−/− mice were found to be more susceptible to infection with Escherichia coli as compared to wild-type mice. Thus, the regulatory functions of RIG-I are strikingly broad, including a role not only in antiviral responses but in antibacterial responses as well

Association of ABCC2 −24C>T Polymorphism with High-Dose Methotrexate Plasma Concentrations and Toxicities in Childhood Acute Lymphoblastic Leukemia

<div><p>Methotrexate (MTX) is a key agent for the treatment of childhood acute lymphoblastic leukemia (ALL). Increased MTX plasma concentrations are associated with a higher risk of adverse drug effects. ATP-binding cassette subfamily C member 2 (ABCC2) is important for excretion of MTX and its toxic metabolite. The <i>ABCC2</i> −24C>T polymorphism (rs717620) reportedly contributes to variability of MTX kinetics. In the present study, we assessed the association between the <i>ABCC2</i> −24C>T polymorphism and methotrexate (MTX) toxicities in childhood ALL patients treated with high-dose MTX. A total of 112 Han Chinese ALL patients were treated with high-dose MTX according to the ALL-Berlin-Frankfurt-Muenster 2000 protocol. Our results showed that presence of the <i>−24T</i> allele in <i>ABCC2</i> gene led to significantly higher MTX plasma concentrations at 48 hours after the start of infusion, which would strengthen over repeated MTX infusion. The <i>−24T</i> allele in <i>ABCC2</i> gene was significantly associated with higher risks of high-grade hematologic (leucopenia, anemia, and thrombocytopenia) and non-hematologic (gastrointestinal and mucosal damage/oral mucositis) MTX toxicities. This study provides the first evidence that the <i>−24T</i> allele in <i>ABCC2</i> gene is associated with the severity of MTX toxicities, which add fresh insights into clinical application of high-dose MTX and individualization of MTX treatment.</p></div

Incidence of methotrexate (MTX) toxicity by ATP-binding cassette subfamily C member 2 (<i>ABCC2</i>) gene −24C>T genotype.

<p>Incidence of methotrexate (MTX) toxicity by ATP-binding cassette subfamily C member 2 (<i>ABCC2</i>) gene −24C>T genotype.</p

Methotrexate (MTX) plasma concentrations by single nucleotide polymorphism (SNP) genotypes of ATP-binding cassette subfamily C member 2 (<i>ABCC2), ABCC4 and ABCG2</i>.

<p>MTX plasma concentrations were measured at 48<i>ABCC4</i> rs9516519 (<i>A</i>), <i>ABCC4</i> rs868853 (<i>B</i>), <i>ABCC4</i> rs2274407 (<i>C</i>), <i>ABCC2</i> rs3740065 (<i>D</i>), <i>ABCG2</i> rs2231137 (<i>E</i>).</p

Characteristics of patients.

<p>Characteristics of patients.</p

Association of ATP-binding cassette subfamily C member 2 (<i>ABCC2</i>) gene −24C>T genotype with methotrexate (MTX) toxicity grades.

<p>Association of ATP-binding cassette subfamily C member 2 (<i>ABCC2</i>) gene −24C>T genotype with methotrexate (MTX) toxicity grades.</p

Methotrexate (MTX) plasma concentrations by ATP-binding cassette subfamily C member 2 (<i>ABCC2</i>) −24C>T polymorphism genotypes.

<p>MTX plasma concentrations were measured at 48<i>ABCC2</i> −24C>T polymorphism genotypes alone (<i>A</i>) or further stratified by gender (<i>B</i>). *<i>p</i><0.05 vs CC.</p

Effects of ATP-binding cassette subfamily C member 2 (<i>ABCC2</i>) gene −24C>T genotype and time on methotrexate (MTX) plasma concentration.

<p>Effects of ATP-binding cassette subfamily C member 2 (<i>ABCC2</i>) gene −24C>T genotype and time on methotrexate (MTX) plasma concentration.</p