The mitogen-activated protein kinase (MAPK) p38/MAPK-activated protein kinase 2 (MK2) signaling pathway plays an important role in the posttranscriptional regulation of tumor necrosis factor (TNF), which is dependent on the adenine/uridine-rich element (ARE) in the 3 untranslated region of TNF mRNA. After lipopolysaccharide (LPS) stimulation, MK2-deficient macrophages show a 90% reduction in TNF production compared to the wild type. Tristetraprolin (TTP), a protein induced by LPS, binds ARE and destabilizes TNF mRNA. Accordingly, macrophages lacking TTP produce large amounts of TNF. Here, we generated MK2/TTP double knockout mice and show that, after LPS stimulation, bone marrow-derived macrophages produce TNF mRNA and protein levels comparable to those of TTP knockout cells, indicating that in the regulation of TNF biosynthesis TTP is genetically downstream of MK2. In addition, we show that MK2 is essential for the stabilization of TTP mRNA, and phosphorylation by MK2 leads to increased TTP protein stability but reduced ARE affinity. These data suggest that MK2 inhibits the mRNA destabilizing activity of TTP and, in parallel, codegradation of TTP together, with the target mRNA resulting in increased cellular levels of TTP.

Brain injuries can interrupt descending neural pathways that convey motor commands from the cortex to spinal motoneurons. Here, we demonstrate that a unilateral injury of the hindlimb sensorimotor cortex of rats with completely transected thoracic spinal cord produces hindlimb postural asymmetry with contralateral flexion and asymmetric hindlimb withdrawal reflexes within 3 hr, as well as asymmetry in gene expression patterns in the lumbar spinal cord. The injury-induced postural effects were abolished by hypophysectomy and were mimicked by transfusion of serum from animals with brain injury. Administration of the pituitary neurohormones β-endorphin or Arg-vasopressin-induced side-specific hindlimb responses in naive animals, while antagonists of the opioid and vasopressin receptors blocked hindlimb postural asymmetry in rats with brain injury. Thus, in addition to the well-established involvement of motor pathways descending from the brain to spinal circuits, the side-specific humoral signaling may also add to postural and reflex asymmetries seen after brain injury.

26A paradigm in neurology is that brain injury-induced motor deficits (e.g. hemiparesis and 27 hemiplegia) arise due to aberrant activity of descending neural pathways. We discovered that a 28 unilateral injury of the hindlimb sensorimotor cortex of rats with completely transected thoracic 29 spinal cord produces hindlimb postural asymmetry with contralateral flexion, and asymmetric 30 changes in nociceptive hindlimb withdrawal reflexes and gene expression patterns in lumbar spinal 31 cord. The injury-induced postural effects were abolished by prior hypophysectomy and were 32 mimicked by transfusion of serum from animals with unilateral brain injury. Antagonists of the 33 opioid and vasopressin receptors blocked formation of hindlimb postural asymmetry suggesting 34 that these neurohormones mediate effects of brain injury on lateralized motor responses. Our data 35 indicate that descending neural control of spinal circuits is complemented by a previously 36 unknown humoral signaling from injured brain to the contra-and ipsilesional hindlimbs, and 37 suggest the existence of a body side-specific neuroendocrine regulation in bilaterally symmetric 38 animals. 39 In this study we challenge the neurological paradigm by investigating whether a unilaterally 62 injured brain may signal to the lumbar spinal cord through non-spinal mechanism. We applied a 63 "reversed strategy" protocol in which brain injury was performed after complete transection of the 64 spinal cord at a superior thoracic level. 65 66 Results 67Brain injury induces postural asymmetry in rats with transected spinal cord 68 We first demonstrated that the unilateral injury of the hindlimb representation area of the 69 sensorimotor cortex in rats induces formation of HL-PA (Figure 1A,D,E; Figure 1-figure 70 supplement 1). The effect was evident under pentobarbital anesthesia within 5 min after the lesion 71 and lasted for 14 days. The HL-PA median values and probability to develop HL-PA greater than 72 the 1 mm threshold were markedly higher in rats with UBI (n = 8) compared to those with sham 73 surgery (sham; n = 7). The UBI rats displayed a contralesional hindlimb flexion which correlated 74 with motor deficits of the same limb in the beam-working and ladder rung tests (UBI, n = 11/12; 75 sham, n = 8) (Figure 1B,C). The UBI rats showed the high number of slips of the contralesional 76 hindlimb compared to the ipsilesional limb, and to both hindlimbs in rats with sham surgery. 77 Consistent with earlier studies (Chamberlain et al., 1963; DiGiorgio, 1929; Hultborn & Malmsten, 78 1983; Rossignol & Frigon, 2011;Wolpaw, 2012), the HL-PA was retained after complete 79 transection of the spinal cord performed at the T2-T3 level (Figure 1-figure supplement 1E-G). 80 We hypothesized that the HL-PA is maintained either due to neuroplastic changes in the lumbar 81 spinal cord induced through the descending neural tracts before spinalization, or due to non-spinal 82 cord mediated signaling from the injured brain to the lumbar neural circui...

A positive effect of estradiol on insulin sensitivity has been shown for females and males. Insulin sensitivity is higher in females than in males, and males show a greater tendency to develop metabolic disorders. It is believed that these sex differences are due to a protective effect of estradiol in females, but not in males. Estradiol is a steroid hormone, and its effect is due to the modulation of target gene expression, but the effect of estradiol on the expression of genes encoding insulin signal transduction and glucose transport has not been sufficiently studied. The aim of the study was to compare the molecular mechanisms of the estradiol influence on insulin sensitivity in mice of both sexes. The effect of gonadectomy and estradiol (1 μg/animal, three days) on the expression of insulin signaling cascade genes in muscle, adipose tissue, and liver, as well as on the expression of Fgf21, estradiol receptors (Esr1/2), and transcription factor Stat3 in the liver in female and male mice was investigated. Estradiol levels were lower and glucose blood levels and insulin resistance were higher in Sham operated (Sham) males compared to Sham females. Irs2, Pik3cd, and Esr1/2 mRNA levels were lower in the liver of Sham males than in Sham females. In females, gonadectomy reduced the level of estradiol in the blood, increased insulin resistance and blood glucose levels compared to Sham females. Administration of estradiol to gonadectomized females decreased blood insulin levels and insulin resistance. In males, gonadectomy, on the contrary, increased the blood estradiol level, decreased blood insulin level and insulin resistance. Estradiol did not affect the parameters studied in males. The development of insulin resistance in gonadectomized females was associated with a decreased expression of the Irs2 gene in the liver. Increased insulin sensitivity in gonadectomized males was associated with increased levels of Irs2 and Pik3cd mRNA in the liver. It can be assumed that increasing the level of estradiol in the blood activates the expression of the Irs2 gene in the liver regardless of animal sex. Also, estradiol seems to regulate the transport of glucose in adipose tissue regardless of animal sex: in females and males, an increase in the blood estradiol level was associated with a decrease in the expression of the Slc2a4 gene in adipose tissue. Thus, the effects of estradiol on the expression of insulin cascade genes do not seem to depend on animal sex, but have tissue specificity. Since the molecular mechanism of estradiol influence on the expression of insulin cascade genes in females and males is the same, the cause of sexual differences in insulin sensitivity and the rate of development of metabolic disorders may be a decrease in the level of estradiol in the blood, as well as a decrease in the expression of estradiol receptors in the liver in males compared to females.

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