Alternative activation of macrophages, induced by Th 2 cytokines and glucocorticoids, is essential for the proper functioning of anti-inflammatory immune reactions. To this end, alternatively activated macrophages (aaMF) express a not yet fully unravelled set of genes including cytokines such as alternative macrophage activation-associated CC-chemokine (AMAC)-1 and pattern recognition molecules such as the scavenger receptor CD163. In order to further characterize the molecular repertoire of aaMF, differential gene expression was analyzed by combining subtractive suppression cloning and differential hybridization. We show here that aaMF induced by interleukin (IL)-4 overexpress the prototype extracellular matrix (ECM) protein fibronectin on the mRNA and protein level. This overall increase is accompanied by a shift in fibronectin splice variants from an embryonic to a mature pattern. In addition, the expression of another ECM protein, bIG-H3, is also upregulated by IL-4 in aaMF. In contrast to IL-4 and in line with its inhibitory effect on wound healing, dexamethasone exerts a strongly suppressive effect on fibronectin and bIG-H3 expression. In conclusion, overexpression of ECM proteins induced by IL-4 in macrophages suggests that aaMF may be involved in ECM deposition and tissue remodelling during the healing phase of acute inflammatory reactions and in chronic inflammatory diseases.
The prevalence rates of systemic lupus erythematosus (SLE) may vary within 17-48/100,000 population worldwide. Although population-based epidemiological studies are still missing, the cutaneous variants of lupus erythematosus (LE) are 2-3 times more frequent than SLE itself. The most common age of onset is 20-40 y. Overall, cutaneous LE is regarded as a variant with less severe course and better prognosis. However, CDLE and SCLE last for many years and may lead, like SLE, to severe disability for work and limited life quality; also, a small proportion of patients with cutaneous LE develops SLE during the course of their disease. This implies considerable amount of medical management and costs for the community. Early recognition of cutaneous LE patients at risk to develop SLE and preventive measures against disease triggering factors are important tasks for physicians attending with cutaneous LE patients. It seems that signs of nephropathy, elevated ANA-titers and arthralgias may serve as prognostic predictors for transition into SLE. Characteristic features of cutaneous LE are photosensitivity and female predominance. UV light is a major environmental triggering factor in cutaneous LE. Skin lesions may be induced or preexistent lesions may exacerbate due to UV light in up to 80-90% of all patients. Therefore, socioeconomic counseling of the young patients, for example choice of occupation and sun protection, are essentials in compliant patients. Also, since females are 3-6 times more frequently affected than males, the possibility of hormonal influences including pregnancy and estrogen-containing drugs should be discussed. Risk considerations for females wishing to become pregnant are required, and avoidance of estrogen-containing contraceptives should be recommended.
Isotretinoin is an extremely effective drug if given systemically in severe forms of seborrhoea and acne, being the only retinoid with potent sebostatic properties. Its unique activity on the sebaceous gland still remains unclear since isotretinoin barely binds to cellular retinoic-acid-binding proteins and to retinoic acid receptors. Its bioavailability is approximately 25% and can be increased by food 1.5–2 times; after 30 min, the drug is detectable in the blood and maximal concentrations are reached 2–4 h after oral intake. The major metabolites of isotretinoin in blood are 4-hydroxy- and 4-oxo-isotretinoin, while several glucuronides are detectable in the bile. 4-Oxo-isotretinoin is present in plasma in a 2- to 4-fold higher concentration 6 h after a single dose. Steady-state concentrations appear after 1 week. The half-life elimination rate of the parent compound ranges from 7 to 37 h while that of some metabolites does so from 11 to 50 h. Isotretinoin crosses the placenta and is recognized as a strong teratogenic compound. About 10–30% of the drug is metabolized via its isomer tretinoin. Excretion of isotretinoin occurs after conjugation with the faeces or after metabolization with the urine. The epidermal levels of isotretinoin are rather low and no progressive accumulation, either in serum or in the skin, is found. After discontinuation of therapy, isotretinoin disappears from serum and skin within 2–4 weeks. Isotretinoin is the most effective drug in reducing sebaceous gland size (up to 90%) by decreasing proliferation of basal sebocytes, suppressing sebum production and inhibiting sebocyte differentiation in vivo. The molecular basis for its antisebotrophic activity has not been fully elucidated. Isotretinoin also exhibits anti-inflammatory activities. Systemic isotretinoin is today the regimen of choice in severe seborrhoea, since it reduces sebocyte lipid synthesis by 75% with daily doses as low as 0.1 mg/kg after 4 weeks. Patients who have received oral isotretinoin therapy for seborrhoea do not usually experience a relapse for months or years. In severe acne, a 6- to 12-month treatment with isotretinoin 1 mg/kg/day reduced to 0.5 or 0.2 mg/kg/day according to the response is recommended (cumulative dose of >120 mg/kg). Contraception is essential during isotretinoin treatment in women of childbearing age 1 month before, during and for 3 months after discontinuation of treatment.
Summary Overexpression of transforming growth factor-4 isoforms (TGF-f1, -P2, -,B3) has been previously reported in human melanoma cell lines and tumours. The aim of the present study was to evaluate the plasma levels of TGF-f isoforms in melanoma patients. Significantly elevated levels of TGF-,1l (4.2 x the controls, P= 0.0094) and of TGF-,2 (1.5 x the controls, P= 0.012) but not of TGF-13 were measured in patients with disseminated but not locoregional melanoma. These results indicate systemic circulation of potentially immunosuppressive peptides of the TGF-P family in end-stage melanoma patients.
SUMMARYWe compared the immunological functions of interferon-c (IFN-c)-induced, classically activated macrophages (caMW) and of interleukin-4 (IL-4)-and glucocorticoid-induced, alternatively activated macrophages (aaMW) in a human co-culture system in vitro. Proliferation of peripheral blood leucocytes (PBL) or CD4+ T cells mediated by optimal doses of phytohaemagglutinin (PHA) or concanavalin A (Con A) was only marginally influenced by caMW, but was strongly inhibited by aaMW. The degree of lymphocyte proliferation sustained in the presence of caMW was gradually reduced in a dose-dependent fashion by the addition of aaMW. Flow cytometric analysis revealed that expression of costimulatory molecules such as CD11a, CD40, CD54, CD58, CD80 and CD86 did not vary significantly between caMW and aaMW and was low for CD58, CD80 and CD86. As shown by reverse transcriptase-polymerase chain reaction (RT-PCR) analysis, IL-10 was expressed in caMW, aaMW and control macrophages; the level of expression of IL-10 was slightly enhanced in aaMW. Neither neutralizing anti-IL-10 antibodies, indomethacin nor NG-monomethyl--arginine (NMMLA) was able to reverse aaMW-mediated inhibition of lymphocyte proliferation. Of several agents interfering with various second messenger pathways, cAMP and the Ca2+-ionophor A23187 inhibited differentiation of cultured human monocytes into phenotypically mature aaMW expressing MS-1 high molecular weight protein (MS-1-HMWP) and RM 3/1 antigen, and prevented the suppressive action of aaMW on lymphocyte proliferation. In conclusion, these results show that aaMW actively inhibit mitogen-mediated proliferation of PBL and CD4+ T cells independently of the expression of costimulatory molecules and of IL-10, NO or prostaglandin synthesis, and that inhibition of phenotypic differentiation of aaMW is paralleled by a lack of functional maturation. Thus, fully matured aaMW may be functional in down-regulating CD4+ T-cell-mediated immune reactions by an as yet unknown mechanism.
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