Physiological organization of immune response based on the homeostatic mechanism of matrix reprogramming: Implication in tumor and biotechnology

It is accepted that the immune system responds to pathogens with activation of antigen-independent innate and antigen-dependent adaptive immunity. However many immune events do not fit or are even inconsistent with this notion. We developed a new homeostatic model of the immune response. This model consists of four units: a sensor, a regulator, an effector and a rehabilitator. The sensor, macrophages or lymphocytes, recognize pathogenic cells and generate alarm signals. The regulator, antigen-presenting cells, Тregs and myeloid-derived suppressor cells, evaluate the signals and together with sensor cells program the effector. The effector, programmed macrophages and lymphocytes, eliminate the pathogenic cells. The rehabilitator, M2 macrophages, restrict inflammation, provide angiogenesis and reparation of tissue damage, and restore the homeostasis. We suggest the terms “immune matrix” for a biological template of immune responses to pathogens and “matrix reprogramming” for the interdependent reprogramming of different cells in the matrix. In an adequate immune response, the matrix forms a negative feedback mechanism to support the homeostasis. We defined the cellular and phenotypic composition of a tumor immune matrix. A tumor reprograms the homeostatic negative feedback mechanism of matrix into a pathogenic positive feedback mechanism. M2 macrophages play a key role in this transformation. Therefore, macrophages are an attractive target for biotechnology. Based on our hypotheses, we are developing a cell biotechnology method for creation of macrophages with a stable antitumor phenotype. We have shown that such macrophages almost doubled the survival time of mice with tumor.     

Susceptibility to Toxoplasma gondii proliferation in BeWo human trophoblast cells is dose-dependent of macrophage migration inhibitory factor (MIF), via ERK1/2 phosphorylation and prostaglandin E2 production

Introduction

Macrophage migration inhibitory factor (MIF) participates in the immune response to Toxoplasma gondii, triggers ERK1/2 and prostaglandin E₂ (PGE₂) activation, but there is limited information on these mechanisms in human trophoblast. The present study aimed to verify the role of MIF in the ERK1/2 phosphorylation and PGE₂ production, as well as its effect on the susceptibility to T. gondii in BeWo cells.

Methods

BeWo cells were treated with increasing concentrations of recombinant MIF (rMIF) and/or T. gondii-soluble tachyzoite antigen (STAg) and analyzed for ERK1/2 phosphorylation and PGE₂ production by Western blotting and ELISA, respectively. Cells were also treated with increasing concentrations of rMIF, rPGE₂, or ERK1/2 inhibitor and tested for T. gondii proliferation. The supernatants of cells treated with rPGE₂ were assayed for cytokine production by ELISA or CBA.

Results

ERK1/2 phosphorylation and PGE₂ production increased when the cells were treated with low MIF concentrations while the parasitism control occurred only at high MIF concentrations. STAg was unable to change ERK1/2 phosphorylation or PGE₂ release. BeWo cells demonstrated increased T. gondii proliferation and reduced production of pro-inflammatory cytokines when treated with PGE₂, while PD98059 diminished the parasite proliferation.

Discussion

The intracellular mechanisms triggered by MIF are dose-dependent in BeWo cells, and PGE₂ is an important factor for the persistence of T. gondii at the maternal fetal interface.

Conclusion

MIF was unable to control T. gondii infection in BeWo cells at low concentrations since ERK1/2 and PGE₂ expression were activated, demonstrating a critical effect of these mediators favoring parasite proliferation.     

Antiparkinsonian activity of L-propyl-L-leucyl-glycinamide or melanocyte-inhibiting factor in MPTP-treated common marmosets.

The neuropeptide melanocyte-inhibiting factor (MIF) or L-propyl-L-leucyl-glycinamide (PLG) has been reported in some studies to improve the motor signs of Parkinson's disease (PD) and in rodent models of PD. In this study of oral and intravenous MIF in N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmosets, a wide range of doses of MIF administered alone (0.25, 1, 2, 5, 10, 20 mg/kg orally) did not increase locomotor activity, relieve motor disability, or induce dyskinesias. When MIF (1.0 and 5.0 mg/kg orally or 10 and 20 mg/kg intravenously) was administered concomitantly with levodopa/benserazide, no significant differences in motor function or dyskinesias were observed compared with levodopa/benserazide alone. The results of this first study of MIF in the marmoset MPTP model provide no encouragement for the reinvestigation of MIF in the clinical management of the motor signs of PD.     

Radiation-induced lung damage promotes breast cancer lung-metastasis through CXCR4 signaling

Radiotherapy is a mainstay in the postoperative treatment of breast cancer as it reduces the risks of local recurrence and mortality after both conservative surgery and mastectomy. Despite recent efforts to decrease irradiation volumes through accelerated partial irradiation techniques, late cardiac and pulmonary toxicity still occurs after breast irradiation. The importance of this pulmonary injury towards lung metastasis is unclear. Preirradiation of lung epithelial cells induces DNA damage, p53 activation and a secretome enriched in the chemokines SDF-1/CXCL12 and MIF. Irradiated lung epithelial cells stimulate adhesion, spreading, growth, and (transendothelial) migration of human MDA-MB-231 and murine 4T1 breast cancer cells. These metastasis-associated cellular activities were largely mimicked by recombinant CXCL12 and MIF. Moreover, an allosteric inhibitor of the CXCR4 receptor prevented the metastasis-associated cellular activities stimulated by the secretome of irradiated lung epithelial cells. Furthermore, partial (10%) irradiation of the right lung significantly stimulated breast cancer lung-specific metastasis in the syngeneic, orthotopic 4T1 breast cancer model.Our results warrant further investigation of the potential pro-metastatic effects of radiation and indicate the need to develop efficient drugs that will be successful in combination with radiotherapy to prevent therapy-induced spread of cancer cells.     

益气补肺方对急性肺损伤大鼠ET-1和MIF水平的影响

目的探讨益气补肺方对油酸性急性肺损伤大鼠的ET-1和MIF水平及肺组织学的影响及保护机制。方法将动物随机分为五组：中药组、西药组、中＋西药组、模型组、正常组。用油酸诱发急性肺损伤，观察造模后大鼠肺系数、肺组织匀浆ET-1和MIF水平、肺组织学改变。结果与油酸组比较，中药组与中＋西药组ET-1和MIF水平明显降低（P〈0．05），其中3组用药组间ET-1水平差异具有显著性（P〈0．05）。结论益气补肺方对油酸诱发的大鼠急性肺损伤有一定的保护作用，抑制ET-1和MIF生成是其作用机制之一。     

Association of genetic polymorphisms of macrophage inhibitory factor (MIF) and B-cell activating factor (BAFF) with the detection of donor specific antibodies in kidney allograft recipients

The posttransplant development of donor specific antibodies (DSA) initiates the antibody mediated rejection (AMR), which is associated with the increased rate of graft loss. One of the characteristics of AMR is the infiltration of innate immune system including macrophages, monocytes, neutrophils or NK cells. Macrophage inhibitory factor (MIF) and B-cell activating factor (BAFF) are well known cytokines that are associated with the activation of the innate immune system which can damage kidney allograft. In this article, the association of the genetic polymorphisms of MIF and BAFF with the development of DSA including Class I and II in kidney transplant patients is investigated. A total of 231 renal transplant patients between 2008 and 2012 at St. Vincent Medical Center, CA were studied in a retrospective study design. DSA were determined by Luminex technology, and single nucleotide polymorphisms (SNP) of MIF and BAFF were determined by the real time PCR based on 5′ nuclease allelic discrimination assay. The genetic polymorphisms of MIF rs1007888 (C/T) was associated with increased risk of positive DSA detection (p = 0.04) after transplantation, and consistently significant after 1 year (p = 0.016). Furthermore, the presence of C allele were associated with the increased risk of Class I DSA detection (OR 1.816, CI 1.141–2.889, p = 0.011). Also, genetic polymorphisms of BAFF rs12583006 were associated with the increased risk of Class II DSA detection (p = 0.033). In conclusion, the genetic polymorphisms of MIF and BAFF may increase the risk of posttransplant development of DSA. This result suggests the association between the development of posttransplant DSA and the activation of innate immune system.     

卵巢癌组织中移动抑制因子的表达与微血管密度的关系

目的:探讨MIF对卵巢癌血管生成的影响,术前化疗是否干扰癌细胞表达MIF。方法:选取原发上皮性卵巢癌组织蜡块58例(其中术前化疗28例)为实验组,19例正常卵巢及单纯卵巢囊肿为对照组,采用SP免疫组织化学法检测组织中MIF和CD34的表达。结果:实验组MIF表达阳性率为84.5%,与对照组(10.5%)相比差异显著(P<0.000 1)。MIF阳性癌组织的微血管密度(MVD)为(34.6±7.1)条/HP,明显高于MIF阴性组织的(20.1±6.7)条/HP及对照组的(12.0±7.5)条/HP(P值均<0.01);MIF表达强度与MVD相关(r=0.67,P<0.05)。实验组内,术前未化疗组(80.0%)与化疗组(89.3%)相比,晚期卵巢癌(88.9%)与早期卵巢癌(69.2%)相比,低分化(90.6%)与高中分化(76.9%)相比,MIF阳性率均无显著差异(P值均>0.05)。结论:MIF具有促进肿瘤组织新生血管形成的作用。化疗对癌组织MIF的表达无明显影响。     

血浆巨噬细胞移动抑制因子水平变化与ST段拾高型心肌梗死患者多因素相关性分析及远期预后

目的探讨血浆巨噬细胞移动抑制因子(macrophage migrationinhibitory factor,MIF)水平变化与ST段抬高型心肌梗死(ST-segment elevated myocardial infarction,STEMI)患者多因素相关性分析及远期预后。方法选择2013年3月-2015年3月内蒙古医科大学附属医院急诊内科收治的168例STEMI患者作为研究组,于术前、术后24h及72h采血测定血浆MIF水平,另选同期稳定性心绞痛(SAP)患者54例、健康体检者72名作为对照组,于就诊时采血测定血浆MIF水平,并分析STEMI患者血浆MIF水平与临床指标及远期预后的相关性。结果STEMI组术前血浆MIF水平显著高于SAP组及健康组(P<0.05);STEMI组术后72h血浆MIF水平与术前、术后24h比较有显著差异(P<0.05);术前MIF水平与高敏肌钙蛋白T(high-sensitive troponin T,hs-TnT)峰值、肌酸激酶同工酶MB(creatine kinase-MB,CK-MB)、高敏C反应蛋白(hs-CRP)、N末端B型利钠肽原(NT-proBNP)呈正相关(P<0.05),与左心室射血分数(LVEF)呈负相关(P<0.05);术前MIF高水平组患者发生前壁、下壁、后壁、侧壁心肌梗死和Kllp≥2级比例显著高于术前MIF低水平组患者(P<0.05);STEMI患者术前、术后24h、术后72h的MIF水平与术前、术后24h、术后72h的中性粒细胞数、白细胞数、单核细胞数呈正相关(P<0.05);STEMI患者术前、术后24h、术后72h的MIF水平与术前、术后24 h、术后72h的淋巴细胞数无相关性(P>0.05);术前MIF高水平(≥53.05 ng/mL)患者发生主要不良心脑血管事件(MACCE)风险显著高于术前MIF低水平(<53.05 ng/mL)患者,有统计学差异(P<0.05)。结论STEMI患者早期血浆MIF水平显著升高,与心功能指标及单核细胞数相关,且就诊时MIF高水平为STEMI患者远期预后不良的独立预测因素。