Membrane-Bound TNF Induces Protective Immune Responses to M. bovis BCG Infection: Regulation of memTNF and TNF Receptors Comparing Two memTNF Molecules

Several activities of the transmembrane form of TNF (memTNF) in immune responses to intracellular bacterial infection have been shown to be different from those exerted by soluble TNF. Evidence is based largely on studies in transgenic mice expressing memTNF, but precise cellular mechanisms are not well defined and the importance of TNF receptor regulation is unknown. In addition, memTNF activities are defined for a particular modification of the extracellular domain of TNF but a direct comparison of different mutant memTNF molecules has not been done in vivo

Pharmacological Stimulation of Edar Signaling in the Adult Enhances Sebaceous Gland Size and Function

Impaired ectodysplasin A (EDA) receptor (EDAR) signaling affects ectodermally derived structures including teeth, hair follicles, and cutaneous glands. The X-linked hypohidrotic ectodermal dysplasia (XLHED), resulting from EDA deficiency, can be rescued with lifelong benefits in animal models by stimulation of ectodermal appendage development with EDAR agonists. Treatments initiated later in the developmental period restore progressively fewer of the affected structures. It is unknown whether EDAR stimulation in adults with XLHED might have beneficial effects. In adult Eda mutant mice treated for several weeks with agonist anti-EDAR antibodies, we find that sebaceous gland size and function can be restored to wild-type levels. This effect is maintained upon chronic treatment but reverses slowly upon cessation of treatment. Sebaceous glands in all skin regions respond to treatment, although to varying degrees, and this is accompanied in both Eda mutant and wild-type mice by sebum secretion to levels higher than those observed in untreated controls. Edar is expressed at the periphery of the glands, suggesting a direct homeostatic effect of Edar stimulation on the sebaceous gland. Sebaceous gland size and sebum production may serve as biomarkers for EDAR stimulation, and EDAR agonists may improve skin dryness and eczema frequently observed in XLHED

Pharmacological stimulation of Edar signaling in the adult enhances sebaceous gland size and function

Impaired ectodysplasin A (EDA) receptor (EDAR) signaling affects ectodermally derived structures including teeth, hair follicles, and cutaneous glands. The X-linked hypohidrotic ectodermal dysplasia (XLHED), resulting from EDA deficiency, can be rescued with lifelong benefits in animal models by stimulation of ectodermal appendage development with EDAR agonists. Treatments initiated later in the developmental period restore progressively fewer of the affected structures. It is unknown whether EDAR stimulation in adults with XLHED might have beneficial effects. In adult Eda mutant mice treated for several weeks with agonist anti-EDAR antibodies, we find that sebaceous gland size and function can be restored to wild-type levels. This effect is maintained upon chronic treatment but reverses slowly upon cessation of treatment. Sebaceous glands in all skin regions respond to treatment, although to varying degrees, and this is accompanied in both Eda mutant and wild-type mice by sebum secretion to levels higher than those observed in untreated controls. Edar is expressed at the periphery of the glands, suggesting a direct homeostatic effect of Edar stimulation on the sebaceous gland. Sebaceous gland size and sebum production may serve as biomarkers for EDAR stimulation, and EDAR agonists may improve skin dryness and eczema frequently observed in XLHED.</p

Perinatal exposure to bisphenol A increases adult mammary gland progesterone response and cell number

Bisphenol A [BPA, 2,2,-bis (hydroxyphenyl) propane] is one of the highest-volume chemicals produced worldwide. It is detected in body fluids of more than 90% of the human population. Originally synthesized as an estrogenic compound, it is currently utilized to manufacture food and beverage containers resulting in uptake with food and drinks. There is concern that exposure to low doses of BPA, defined as less than or equal to 5 mg/kg body weight /d, may have developmental effects on various hormone-responsive organs including the mammary gland. Here, we asked whether perinatal exposure to a range of low doses of BPA is sufficient to alter mammary gland hormone response later on in life, with a possible impact on breast cancer risk. To mimic human exposure, we added BPA to the drinking water of C57/Bl6 breeding pairs. Analysis of the mammary glands of their daughters at puberty showed that estrogen-dependent transcriptional events were perturbed and the number of terminal end buds, estrogen-induced proliferative structures, was altered in a dose-dependent fashion. Importantly, adult females showed an increase in mammary epithelial cell numbers comparable to that seen in females exposed to diethylbestrol, a compound exposure to which was previously linked to increased breast cancer risk. Molecularly, the mRNAs encoding Wnt-4 and receptor activator of nuclear factor kB ligand, two key mediators of hormone function implicated in control of mammary stem cell proliferation and carcinogenesis, showed increased induction by progesterone in the mammary tissue of exposed mice. Thus, perinatal exposure to environmentally relevant doses of BPA alters long-term hormone response that may increase the propensity to develop breast cancer. © 2011 by The Endocrine Society.Swiss Science Foundation (NRP50); Swiss Federal Public Health Offic

Antigen-specific IFN-γ and nitric oxide release from splenocytes of <i>M. bovis</i> BCG-infected mice.

<p>IFN-γ and NO (nitric oxide) were evaluated in culture supernatant from cells incubated with antigens derived from <i>M. bovis</i> BCG (A and C) or with 10³ viable <i>M. bovis</i> BCG (B and D). Values are represented as mean ± <i>SEM</i> (<i>n</i> = 3 animals per group, assayed in triplicate). * p<0.04.</p

Decreased iNOS protein in memTNF KI but similar number of splenic CD11b⁺/TNF⁺ cells 4 weeks after <i>M. bovis</i> BCG infection.

<p>(A) Spleen iNOS protein expression was detected by western blot 4 weeks after <i>M. bovis</i> BCG infection. (B) iNOS protein was quantified by Image Quant software. Results are expressed as mean ± SEM of relative units of iNOS/actin (<i>n</i> = 4, except for TNFR1/TNFR2−/− mice <i>n</i> = 2 per group). *, p<0.04. FACS analyses showing the number of CD11b⁺ cells (C) and of CD11b⁺/TNF⁺ (D) in the spleen of uninfected, 2 and 4 weeks infected mice. Results are shown as mean ± SEM of positive cells per spleen (<i>n</i> = 4). *, p<0.01 compared to wild-type mice.</p

<i>M. tuberculosis</i> and <i>M. bovis</i> BCG infection studies performed in memTNF KI mice.

<p><i>M. tuberculosis</i> and <i>M. bovis</i> BCG infection studies performed in memTNF KI mice.</p

Decreased pulmonary phosphorylated p65 NF-κB in memTNF^Δ1–12 KI mice after 2 weeks of <i>M. bovis</i> BCG infection.

<p>(A) Phosphorylated and unphosphorylated p65 NF-κB and actin protein expressions were detected in lungs by western blot 2 weeks after <i>M. bovis</i> BCG infection. (B) Quantification of phosphorylated and unphosphorylated p65 NF-κB on western blot was done by Quantity One® analysis software on two different experiments. Results are expressed as mean ± SEM of relative units of phosphorylated p65 NF-κB/total p65 NF-κB (<i>n</i> = 4–5 mice/group) (*, p<0.02).</p

Survival curve, body weight and bacterial loads in lung and liver of mice infected with 10⁷CFU of <i>M. bovis</i> BCG.

<p>(A) Long-term survival of mice infected with living <i>M. bovis</i> BCG Connaught (10⁷). (B) Body weight change after <i>M. bovis</i> BCG infection. Wild-type and memTNF^Δ1–9,K11E KI, (<i>n</i> = 14 mice per group), memTNF^Δ1–12 (<i>n</i> = 10 mice), and TNF−/− mice (<i>n</i> = 6 per group). Data from two representative experiments are shown. CFU were determined in lungs (C, D) and liver (E, F) at 2 and 4 weeks after infection with 10⁷ CFU of <i>M. bovis</i> BCG. Data are represented as individual values and horizontal bars indicate mean (<i>n</i> = 4–6 mice per group). Asterisks indicate statistically significant differences between wild type and indicated group (*, p<0.03).</p