The Underlying Mechanism of Duanteng Yimu Decoction in Inhibiting Synovial Hyperplasia in Rheumatoid Arthritis.

Dysregulation of microRNAs (miRNAs) is associated with the pathogenesis of rheumatoid arthritis (RA). Our previous studies confirmed that Duanteng Yimu decoction (DTYMT) effectively inhibits RA fibroblast-like synoviocyte (FLS) proliferation. In this study, we investigated the influence of DTYMT on miR-221 in RA individuals. Hematoxylin-eosin (HE) staining was performed to assess histopathological alterations in collagen-induced arthritis (CIA) mice. The expression of miR-221-3p and TLR4 in PBMC, FLS, and cartilage was measured by RT-qPCR. In the in vitro experiments, DTYMT-containing serum was incubated with FLS-transfected miR-221 mimic or inhibitor. CCK-8 was performed to determine FLS proliferation, and the secretion of IL-1ß, IL-6, IL-18, and TNF-α was quantified by ELISA assay. In addition, the regulation of miR-221 expression on FLS apoptosis was assessed using flow cytometry. Finally, western blot was employed to reflect TLR4/MyD88 protein levels. HE results showed that DTYMT effectively reduced synovial hyperplasia in the joints of CIA mice. RT-qPCR assay of FLS and cartilage of the model group showed that miR-221-3p and TLR4 significantly increased compared with those in the normal group. All outcomes were improved by DTYMT. The miR-221 mimic reversed the inhibitory effect of DTYMT-containing serum on FLS proliferation, the release of IL-1ß, IL-18, IL-6, and TNF-α, and FLS apoptosis, as well as TLR4/MyD88 protein levels. The results showed that miR-221 promotes the activity of RA-FLS by activating TLR4/MyD88 signaling, and DTYMT treats RA by reducing miR-221 in CIA mice.

Mechanism underlying the action of Duanteng-Yimu Tang in regulating Treg/Th17 imbalance and anti-rheumatoid arthritis.

Background: Rheumatoid arthritis (RA) is a chronic immune disease characterised by synovitis and cartilage destruction. Currently, many patients experience poor remission after new antirheumatic drug treatments. Duanteng-Yimu Tang (DTYMT), a traditional Chinese medicine, is effective in the treatment of RA. In this research, we designed to investigate the anti-RA effects of DTYMT and explore its potential mechanisms. Methods: Network pharmacology was adopted to explore the main pathways of DTYMT in patients with RA. Collagen-induced arthritis models of male DBA/1 mice were established, and their histopathological changes were observed by hematoxylin-eosin staining and micro-CT. qRT-PCR was performed to detect the expression of Foxp3 and RORγt in the serum and synovial tissue and IL-17, IL-1ß, TNF-α, and IL-10 mRNA in vivo. The proliferation and invasion of synovial cells were analyzed using Cell Counting Kit-8 and transwell assays, respectively. The ratio of T helper 17 (Th17) to regulatory T (Treg) cells was analyzed by flow cytometry. Results: Network pharmacology analysis revealed that Th17 cell differentiation may be the key pathway of DTYMT in RA. DTYMT ameliorated joint damage, inhibited RORγt expression, and increased Foxp3 expression in CIA mice. DTYMT significantly decreased IL-1ß, IL-17, and TNF-α mRNA levels, and increased IL-10 mRNA levels in IL-6-induced cells. Additionally, DTYMT inhibited Th17 cell differentiation and promoted Treg cell production, thus improving the Treg/Th17 imbalance. DTYMT also inhibited the proliferation, migration, and invasion of RA fibroblast-like synovial cells. Conclusions: These results indicate that DTYMT could regulate the Treg/Th17 cell balance, which is a possible mechanism of DTYMT in treating RA.

Clinical observation on the treatment of ankle fracture with buttress plate and traditional internal fixation and its effect on GQOLI-74 score and Baird-Jackson score.

Objective: To explore the curative effect of buttress plate and traditional internal fixation in the treatment of ankle fracture, so as to provide potential reference for the clinical treatment of this disease. Methods: This is a clinical comparative study. The subjects of this study were one hundred patients with ankle fracture treated in Mindong Hospital Affiliated to Fujian Medical University from January 2019 to December 2021. Enrolled patients were randomly divided into the control group and the experimental group. Patients in the control group were treated with traditional internal fixation, and those in the experimental group were provided with buttress plate. Patients were compared in several aspects such as the comprehensive quality of life assessment questionnaire (GQOLI-74), Baird-Jackson score and postoperative complications. Result: The experimental group showed improved Baird-Jackson score after treatment, significantly higher fracture healing rate than that of the control group three months after treatment. Besides, there was no significant difference in the complications between the two groups, with good prognosis after timely treatment. Conclusion: Internal fixation with buttress plate has obvious advantages in the treatment of ankle fractures, which can effectively improve the quality of life and promote the rapid healing of fractures. It is worthy of clinical promotion and application.

Study on the effect and mechanism of quercetin in treating gout arthritis.

Quercetin is widely found in natural plants, especially Chinese herbal plants. It has been used to treat arthritis in China for thousands of years. However, the effects and mechanisms of quercetin in the treatment of gout arthritis (GA) remain unclear. We aimed to verify the treatment of GA with quercetin and investigate the underlying mechanism. A combination of network pharmacology and experiments was used to reveal the mechanism of quercetin in the treatment of GA. Potential targets of quercetin and gout were identified. Then, the protein-protein interaction network for the common targets between quercetin and gout was constructed and the core targets were identified. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses for the common targets were performed to elucidate the pharmacological functions and mechanisms associated with quercetin treatment in GA. Finally, a monosodium urate-induced GA rat model was used to validate the predicted mechanisms in network pharmacology. Seventy-two common targets were identified. KEGG analysis revealed that treatment of GA with quercetin predominantly involved the interleukin (IL)-17, tumor necrosis factor (TNF), mitogen-activated protein kinase, and phosphoinositide 3-kinase-Akt signaling pathways. In an experimental validation, quercetin attenuated ankle joint inflammation-induced bone destruction and histological lesions. It also diminished the expression of IL-6, IL-17A, and IL-17F in the IL-17 pathway, and regulated the release of RAR-related orphan receptor gamma t,IL-17E, IL-1ß, IL-6, TNF-α, Foxp3, and transforming growth factor-beta 1. The collective findings implicate quercetin as a valuable alternative drug for the treatment of GA.

Association between neutrophils and renal impairment of rheumatoid arthritis: A retrospective cross-sectional study.

OBJECTIVE: Previous studies have shown that increased neutrophils, as a manifestation of oxidative stress, may be involved in the progression of kidney disease. To our knowledge, little is known about the relationship between neutrophils and renal impairment in rheumatoid arthritis (RA). Therefore, we aim to investigate whether neutrophil is associated with renal impairment in RA patients. METHODS: We retrospectively investigated the renal function of 602 RA patients in the First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine by estimated glomerular filtration rate (eGFR) from September 2018 and September 2019. The exposure variable was neutrophils, and the main outcome was eGFR. General data (gender, age, duration, hypertension, diabetes, hobbies, and medication history), whole blood markers, lipid indexes, and inflammatory indexes were collected as much as possible. We used multivariable logistic regression analysis to evaluate the association between neutrophils and renal impairment in RA participants. RESULTS: A total of 89 cases (14.8%) had renal impairment with eGFR < 60 ml/min/1.73 m2 , and 75 cases (84.3%) were female. Subgroup analysis showed that female (odds ratio [OR] = 0.523, 95% confidence interval [CI]: 0.318-0.867, p = .011), neutrophils greater thsn 7.5 × 109 /L (OR = 2.314, 95% CI: 1.310-4.087, p = .004), NLR > 3.53 (OR = 1.757, 95% CI: 1.104-2.799, p = .018), hemoglobin less than 120 g/L (OR = 2.413, 95% CI: 1.418-4.118, p = .001), and UA > 360 µmol/L (OR = 6.052, 95% CI: 3.708-9.878, p < .001) was related to renal damage in RA. Adjusted for several confounders, the multivariable analysis indicated that neutrophils greater than 7.5 × 109 /L (OR = 1.784, 95% CI: 1.164-3.288, p = .031) was independently associated with an increased risk of renal impairment in RA. CONCLUSION: Our study demonstrated that neutrophils greater than 7.5 × 109 /L was associated with a high risk of renal impairment in RA, suggesting that neutrophil may be a biomarker for renal impairment in RA.

A super Degasperis-Procesi equation and related integrable systems.

Based on a 4 × 4 matrix spectral problem, a super Degasperis-Procesi (DP) equation is proposed. We show that under a reciprocal transformation, the super DP equation is related to the first negative flow of a super Kaup-Kupershmidt (KK) hierarchy, which turns out to be a particular reduction of a super Boussinesq hierarchy. The bi-Hamiltonian structure of the super Boussinesq hierarchy is established and subsequently produces a Hamiltonian structure, as well as a conjectured symplectic formulation of the super KK hierarchy via suitable reductions. With the help of the reciprocal transformation, the bi-Hamiltonian representation of the super DP equation is constructed from that of the super KK hierarchy. We also calculate a positive flow of the super DP hierarchy and explain its relations with the super KK equation. Infinitely many conservation laws are derived for the super DP equation, as well as its positive flow.

Leonurine Regulates Treg/Th17 Balance to Attenuate Rheumatoid Arthritis Through Inhibition of TAZ Expression.

Leonurine, an active alkaloid extracted from Herba leonuri, is reported to have potent anti-inflammatory activity against rheumatoid arthritis (RA). However, the molecular mechanism of action of leonurine in RA remains poorly understood. In this study, we detected 3,425 mRNAs differentially expressed between CD4+ T cells of RA patients and those of healthy individuals using microarray raw data mining. Kyoto Encyclopedia of Genes and Genomes enrichment analysis revealed that transcriptional coactivator with PDZ-binding motif (TAZ) regulates a variety of biological processes including T-helper (Th)-17 cell development, and was thus selected for functional verification. In a naïve CD4+ T cell differentiation assay, we found that TAZ overexpression was associated with impaired balance between T regulatory (Treg) and Th17 cells in vitro. TAZ overexpression increased the levels of the pro-inflammatory cytokines interleukin (IL)-17, IL-1ß, and tumor necrosis factor (TNF)-α and decreased that of the anti-inflammatory cytokine IL-10. Leonurine treatment had a direct recovery effect on the impaired balance and reduced the expression of TAZ and led to normalization of IL-17, IL-1ß, and TNF-α and IL-10. Furthermore, IL-6 was found to promote the expression of TAZ and receptor activator of nuclear factor kappa-B ligand (RANKL), and RANK. Leonurine significantly inhibited TAZ-mediated expression of RANKL, and RANK and IL-6 in synovial fibroblasts. We conclude that the therapeutic effect of leonurine was through suppression of TAZ led to restoration of Treg/Th17 balance and suppression of synovial fibroblast action.

Presence of lacunar infarctions is associated with the spatial navigation impairment in patients with mild cognitive impairment: a DTI study.

Lacunar cerebral infarction (LI) is one of risk factors of vascular dementia and correlates with progression of cognitive impairment including the executive functions. However, little is known on spatial navigation impairment and its underlying microstructural alteration of white matter in patients with LI and with or without mild cognitive impairment (MCI). Our aim was to investigate whether the spatial navigation impairment correlated with the white matter integrity in LI patients with MCI (LI-MCI). Thirty patients with LI were included in the study and were divided into LI-MCI (n=17) and non MCI (LI-Non MCI) groups (n=13) according neuropsychological tests.The microstructural integrity of white matter was assessed by calculating a fractional anisotropy (FA) and mean diffusivity (MD) from diffusion tensor imaging (DTI) scans. The spatial navigation accuracy, separately evaluated as egocentric and allocentric, was assessed by a computerized human analogue of the Morris Water Maze tests Amunet. LI-MCI performed worse than the CN and LI-NonMCI groups on egocentric and delayed spatial navigation subtests. LI-MCI patients have spatial navigation deficits. The microstructural abnormalities in diffuse brain regions, including hippocampus, uncinate fasciculus and other brain regions may contribute to the spatial navigation impairment in LI-MCI patients at follow-up.

Habitual coffee consumption and risk of cognitive decline/dementia: A systematic review and meta-analysis of prospective cohort studies.

OBJECTIVE: Findings from epidemiologic studies of coffee consumption and risk for cognitive decline or dementia are inconclusive. The aim of this study was to conduct a meta-analysis of prospective studies to assess the association between coffee consumption and the risk for cognitive decline and dementia. METHODS: Relevant studies were identified by searching PubMed and Embase databases between 1966 and December 2014. Prospective cohorts that reported relative risk (RRs) and 95% confidence intervals (CIs) for the association of coffee consumption with dementia incidence or cognitive changing were eligible. Study-specific RRs were combined by using a random-effects model. RESULTS: Eleven prospective studies, including 29,155 participants, were included in the meta-analysis. The combined RR indicated that high coffee consumption was not associated with the different measures of cognitive decline or dementia (summary RR, 0.97; 95% CI, 0.84-1.11). Subgroup analyses suggested a significant inverse association between highest coffee consumption and the risk for Alzheimer disease (summary RR, 0.73; 95% CI, 0.55-0.97). The dose-response analysis, including eight studies, did not show an association between the increment of coffee intake and cognitive decline or dementia risk (an increment of 1 cup/d of coffee consumed; summary RR, 1.00; 95% CI, 0.98-1.02). CONCLUSIONS: The present study suggests that higher coffee consumption is associated with reduced risk for Alzheimer disease. Further randomized controlled trials or well-designed cohort studies are needed to determine the association between coffee consumption and cognitive decline or dementia.

[Analysis of clinical effects of three operative methods for osteoporotic vertebral compression fracture].

OBJECTIVE: To explore the clinical outcomes of percutaneous vertebroplasty(PVP), percutaneous kyphoplasty(PKP) and percutaneous hollow pedicle screw with lateral holes implanted bone cement reinforcement in treating osteoporotic vertebral compression fracture(OVCF). METHODS: From May 2012 to November 2013, the clinical data of 90 patients with osteoporotic vertebral compression fracture were retrospectively analyzed. According to the different methods of operation, the patients were divided into three groups, including the percutaneous hollow pedicle screw with lateral holes implanted bone cement reinforcement group (group A), percutaneous vertebroplasty group (group B), percutaneous kyphoplasty group (group C), each group had 30 patients. Pre operative, postoperative at 1 day, 3 months, 1 year, the back pain was assessed by visual analogue scale(VAS), and vertebral height compression ratio, Cobb angle were measured by X-rays. RESULTS: All operations were successful and no complications such as postoperative infections and deep vein thrombosis were found. At the final follow up, there were 2 patients with mild postoperative back pain in group A;7 patients with moderate postoperative back pain, 4 patients with severe postoperative back pain, 2 patients with postoperative vertebral refracture in group B; 5 patients with moderate postoperative back pain, 3 patients with severe postoperative back pain, 4 patients with postoperative vertebral refracture in group C. Postoperative VAS, vertebral height compression ratio, Cobb angle of all patients have obviously improved than preoperative(P<0.05). On 1 day, 3 months, 1 year after operation, there was significant difference between group A and group B, C(P<0.05), there was no significant difference between group B and group C(P>0.05). There was no significant difference in group A above items and different times(P>0.05), and there was significant difference in group B, C above items and different times(P<0.05). CONCLUSIONS: The effect of PVP and PKP on the immediately postoperative pain relief was more than percutaneous hollow pedicle screw with lateral holes implanted bone cement reinforcement in treating osteoporotic vertebral compression fracture, but, residual back pain can happen in different extent in the patients underwent PVP and PKP. Percutaneous hollow pedicle screw with lateral holes implanted bone cement reinforcement technique has obvious advantage in recovery of the vertebral height, correction of vertebral deformity, reduction of postoperative back pain.

[Anti-fertility effect of Tongbi composition and its reversibility in male rats].

OBJECTIVE: To study the anti-fertility effect of maximum-dose Tongbi Composition and its reversibility in male rats. METHODS: Thirty-six male SD rats were equally randomized into a control group and a medication group, the former given normal saline at 10 ml/(kg x d), while the latter treated with Tongbi Composition at 10 g/(kg x d), both for 60 days. Half the rats of each group were sacrificed randomly at the cessation of treatment, and the rest killed at 72 days after it. The relative testis weight, testis volume, sperm concentration and sperm motility were measured, and the pathological changes in the testicular tissue observed under the optical microscope. RESULTS: After 60 days of treatment, no statistically significant differences were found between the two groups in the relative testis weight, testis volume and sperm concentration (P > 0.05) , and the sperm motility of the medication group dropped to zero, but it was restored to normal at 72 days after drug withdrawal. Almost no lesions were observed in the testis tissue of the medication group. CONCLUSION: The short-term use of Tongbi Composition at the maximum clinical dose has an obvious anti-fertility effect, but it is reversible.

[The apoptosis of mouse macrophage J774A.1 induced by oxysterol depend on NF-kappaB activation].

AIM: Investigated the relationship between NF-kappaB activation and cell apoptosis in mouse macrophages treated with 7-ketochesterol (7-KC). METHODS: Cell apoptosis was detected by MTT assay, DNA fragmentation assay and flow cytometric analysis. NF-kappaB activation was detected by western blot and immunohistochemistry. Inhibitory assay was used to show the effect of the activation of NF-kappaB on the apoptosis induced by 7-KC. RESULTS: 7-KC inhibited macrophages proliferation, and then induced apoptosis, which is associated with NF-kappaB activation. Moreover, cell apoptosis with NF-kappaB activation was inhibited by pyrrolidine dithiocarbamate (PDTC), an inhibitor of NF-kappaB. CONCLUSION: 7-KC induced the activation of NF-kappaB and following cell apoptosis.

[Studies on the oxidation of LDL induced by Cu2 at different time by spectroscopic method].

Oxidized low density lipoprotein (oxLDL) is thought to be a key proatherogenic event. The oxidation of LDL induced by Cu+ at different time was studied by UV-Vis absorption spectra and circular dichroism (CD) spectra. It was shown that long oxidation time is accompanied by an increased MDA content and fluorescence intensity at 430 nm, which suggested new product. The intensity of UV absorption peak of LDL increased, while fluorescence and synchronous fluorescence intensities, which typified amino acids, decreased. CD data displayed that alpha-helical content of the protein decreased and the secondary structure changed. The results indicated that during the process of oxidation of LDL Cu2+ induced not only the product but also the change of the conformation of apoB-100.

[Study on the polymorphism of killer cell immunoglobulin like receptor (KIR) gene with systemic lupus erythematosus of North population in China].

AIM: To investigate the polymorphism of KIR genes in systemic lupus erythematosus (SLE) patients, and to study the correlation between KIR genes and susceptibility of SLE. METHODS: The polymorphism of KIR genes were detected by PCR-SSP technique in 62 patients with SLE and 61 healthy persons as controls from North of China. RESULTS: The differences of KIR frequency between the SLE group and the control were tested by statistical analysis. The most frequent genotype was KIR 3DP1, 2DL1, 2DP1, 3DL1, 2DL3, 1D, followed by 2DS4, 2DL5, 3DS1, 2DS2, 2DS5 and 2DL2. KIR 2DS1, 2DS3 and 3DP1v were lower in frequency compared with others. The frequency of KIR 3DS1, 2DL2, 2DL5 and 2DL3 were significantly lower in SLE group than that in the control èP<0.01é. CONCLUSION: There may be a association between the polymorphism of KIR genes with SLE in North of China should be investigated further.

[Effects of Tongbi Mixture 2 on expressions of CD28 and CD152 and content of tumor necrosis factor-alpha in peripheral blood in rats with collagen-induced arthritis].

OBJECTIVE: To study the effects of Tongbi Mixture 2, a compound traditional Chinese herbal medicine for treating rheumatoid arthritis (RA), on immunoregulation of T lymphocytes in rats with collagen-induced arthritis (CIA). METHODS: Forty Wistar rats were randomly divided into normal control group, untreated group, Tongbi Mixture 2-treated group, methotrexate (MTX)-treated group and Tripterygium wilfordii polyglycoside (TWP)-treated group. Except for the rats of the normal control group (injection with normal saline), rats of the other four groups were subcutaneouly multipoint-injected with collagen protein II to induce CIA. The rats were treated with normal saline, Tongbi Mixture 2, MTX tablets and TWP tablets respectively for 36 days. The expressions of CD28 and CD152 were detected by flow cytometry, while the content of tumor necrosis factor-alpha (TNF-alpha) was analyzed by enzyme-linked immunosorbent assay. RESULTS: The expression of CD28 among the three drug treated groups had no statistical difference (P>0.05), while significantly higher than that of the normal control group (P<0.01) and lower than that of the untreated group (P<0.01). The expression of CD152 in the Tongbi Mixture 2 treated-group was lower than those of the MTX- and TWP-treated groups (P<0.05, P<0.01), but had no statistical difference as compared with the normal control group (P>0.05). There were no statistical differences in content of TNF-alpha between the drug treated groups and the normal control group (P>0.05), but the content of TNF-alpha of the drug treated groups was lower than that of the untreated group (P<0.05 or P<0.01). CONCLUSION: Tongbi Mixture 2 can inhibit T lymphocytes through down-regulating the expressions of CD28 and CD152 and the content of TNF-alpha, which may be the major mechanisms in treating RA.

[Paharmacological mechanisms of cellular immunity of overall alkali of tongbiling for the treatment of joint destruction].

AIM: To investigate the effect of the overall alkali of Traditional Chinese Medicine tongbiling(TBL) which comprises brucine and strychnine alkaloids on collagen induced-arthritis(CIA) and study its paharmacological mechanisms of cellular immunity. METHODS: Bovine CII was emulsified in Freund's incomplete adjuvant. Wistar rats were injected with Type II collagen intradermally at the base of the tail. After swelling, CIA groups were, randomly divided into physiological saline group and treatment group. Then the swelling of the rats' hindlimbs was evaluated. The whole body of the rats treated on 35 th days was photographed by mammography X-Ray. 96 joints in erosion scoring system and 100 joints in joint spacing narrow(JSN) scoring system were used to observe the joint destruction of CIA from X-Ray comprehensively and objectively. After the rats were killed, the third proximal claw pad of the right hindlimb and left forelimb were stained by HE dying, Neutrophil, lymphocyte, plasmacyte infiltration and hyperplasia of synoviocytes were assessed. Then MTT and Western blot were used to determine the effect of the overall alkali of TBL on proliferation of Jurkat cells and ERK1/2 phosphorylation of Jurkat cells, respectively. RESULTS: Inflammation of CIA joints was aggravated quickly. The swelling of CIA rats treated by MTX and overall alkali of TBL for 35 days was relieved (P<0.05). MTX and overall alkali of TBL inhibited the hyperplasia of synoviocytes. Overall alkali of TBL inhibited the infiltration of lymphocyteS and plasmacytes. Overall alkali of TBL inhibited the proliferation and ERK1/2 phosphorylation of Jurkat cells. CONCLUSION: Overall alkali of TBL could relieve joint inflammation and destruction of CIA rats by blocking the MAPK cell signalling pathway to inhibit the activation and proliferation of T cells. Our study might provide an experimental basis for treatment of rheumatoid arthritis with overall alkali of TBL.

[Polymorphism of killer cell immunoglobulin-like receptor gene and its correlation with leukemia].

The study was purposed to investigate the polymorphism of killer cell immunoglobulin-like receptor (KIR) gene of the patients with leukemia and to explore the correlation between the KIR gene and susceptibility of leukemia. The KIR genotype of 50 patients with leukemia and 60 healthy controls in northern. Hans were analyzed by PCR-SSP. The results indicated that the present known 18 KIR genes were detected and identified. The frequencies of KIR 3DL3, 3DL2 and 2DL4 were 100% in all subjects, with the most frequent genotype KIR 3DP1 (0.86) followed by 2DP1, 2DL3, 3DL1, 2DL1, 3DS1, 2DL5, 2DS4, 2DS2, 1D, 2DS5, 2DL2, 2DS1, 2DS3 and 3DP1v in leukemia successively. Compared with the control, the KIR 3DL1 (0.60) and 2DL1 (0.57) were significantly lower in the leukemia patient group than that in the control group (1.00) (P < 0.01). It is concluded that the polymorphism of KIR gene is associated with susceptibility of leukemia in Hans. There may be a negative correlation between pathogenesis of leukemia and KIR 3DL1, KIR 3DS1, KIR 2DL1, KIR 2DL5 genes.

Sf-Stk kinase activity and the Grb2 binding site are required for Epo-independent growth of primary erythroblasts infected with Friend virus.

During the initial stage of Friend virus-induced erythroleukemia in mice, interaction of the viral protein gp55 with the erythropoietin receptor, and other host factors, drives the expansion of erythroid precursor cells. Recently, we demonstrated that the Friend virus susceptibility locus, Fv2, which is required for the expansion of infected cells, encodes a naturally occurring, N-terminally truncated form of the Stk receptor tyrosine kinase (Sf-Stk). Here we show that in vitro expression of Sf-Stk confers Friend virus sensitivity to erythroid progenitor cells from Fv2(rr) mice. Furthermore, our data reveal that Sf-Stk kinase activity and Y436, but not Y429, are required for Epo-independent colony formation following Friend virus infection. Introduction of a mutation that results in failure to bind Grb2 abrogates the ability of Sf-Stk to induce colonies in response to Friend virus, while the Grb2 binding site from EGFR restores this response. Consistent with the ability of Grb2 to recruit SOS and Gab1, the Ras/MAPK and PI3K pathways are activated by Sf-Stk, and both of these pathways are required for gp55-mediated erythroblast proliferation. These data clearly demonstrate a requirement for signaling through Sf-Stk in the Epo-independent expansion of Friend virus-infected cells, and suggest a pivotal role for Grb2 in this response.