In our study, we treated highly differentiated cultures of primary human tracheobronchial epithelial (TBE) cells with a panel of cytokines (interleu- kin-1␣, 1␤, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 15, 16, 17, 18, and tumor necrosis factor ␣). We found that IL-6 and IL-17 could stimulate the mucin genes, MUC5B and MUC5AC. The Th2 cytokines IL-4, IL-9, and IL-13 did not stimulate MUC5AC or MUC5B in our experiments. A similar stimulation of MUC5B/Muc5b expression by IL-6 and IL-17 was demonstrated in primary monkey and mouse TBE cells. Further investigation of MUC5B expression demonstrated that IL-17's effect is at least partly mediated through IL-6 by a JAK2-dependent autocrine/paracrine loop. Finally, evidence is presented to show that both IL-6 and IL-17 mediate MUC5B expression through the ERK signaling pathway.

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An estrogen (E2)-dependent 90,000-92,000 M(r) protein is synthesized and released by the sheep oviduct in a temporally and regionally specific manner during the first few days of pregnancy, where it associates with the embryo. The present study was undertaken to further define the nature of this protein and its regulation at a time when fertilization and early embryonic cleavage occur in the oviduct. The complete complementary DNA (cDNA) sequence for the 90,000-92,000 M(r) protein was determined, and steady state messenger RNA (mRNA) levels were measured during early pregnancy (estrus and days 1, 2, 3, 4, 6, and 16). The composite cDNA possessed an open reading frame of 1633 bases with a single potential N-glycosylation site. The inferred amino acid (aa) sequence predicted a prepolypeptide of 539 aa (69,151 M(r)) and a mature polypeptide of 518 aa (66,477 M(r)). Nucleotide and deduced aa sequence shared identity with translated E2-dependent cow, human, and partially sequenced baboon oviduct protein cDNAs; a human articular cartilage protein, gp 39; and chitinases. Northern blot hybridization revealed a single RNA species (2.2 kilobases) in the fimbria and ampulla, which was not detected in the isthmus or other reproductive and nonreproductive tract tissue RNAs. Steady state levels of mRNA encoding the 90,000-92,000 M(r) were highest in the fimbria and ampulla at estrus and on day 1 of pregnancy, when gamete transport and fertilization occur in the E2-dominated fallopian tube. Oviduct protein mRNA levels declined significantly (P < 0.05) on day 2 and underwent a further significant reduction on day 3 of pregnancy coincident with transport of the embryo from the oviduct to the uterus, a reproductive stage associated with rising progesterone levels. By day 16 of pregnancy, the mRNA encoding the E2-dependent oviduct protein was virtually undetectable. The temporally and regionally specific regulation of gene expression for the 90,000-92,000 M(r) E2-dependent protein correlates with protein synthesis data and emphasizes the precise regulation of its synthesis at a time when fertilization and embryonic cleavage are taking place in the oviduct. Identity with a growing class of steroid-regulated oviduct secretory proteins and chitinase enzymes suggests a possible structural and/or functional relationship, which may be important in mediating these latter reproductive events.

Background-Atherosclerosis is a complex disease requiring improvements in diagnostic techniques and therapeutic treatments. Both improvements will be facilitated by greater exploration of the biology of atherosclerotic plaque. To this end, we carried out large-scale gene expression analysis of human atherosclerotic lesions. Methods and Results-Whole genome expression analysis of 101 plaques from patients with peripheral artery disease identified a robust gene signature (1514 genes) that is dominated by processes related to Toll-like receptor signaling, T-cell activation, cholesterol efflux, oxidative stress response, inflammatory cytokine production, vasoconstriction, and lysosomal activity. Further analysis of gene expression in microdissected carotid plaque samples revealed that this signature is differentially expressed in macrophage-rich and smooth muscle cell-containing regions. A quantitative PCR gene expression panel and inflammatory composite score were developed on the basis of the atherosclerotic plaque gene signature. When applied to serial sections of carotid plaque, the inflammatory composite score was observed to correlate with histological and morphological features related to plaque vulnerability. Conclusions-The robust mRNA expression signature identified in the present report is associated with pathological features of vulnerable atherosclerotic plaque and may be useful as a source of biomarkers and targets of novel antiatherosclerotic therapies. (Circ Cardiovasc Genet. 2011;4:595-604.)Key Words: plaque Ⅲ macrophage Ⅲ smooth muscle cell Ⅲ correlation Ⅲ coexpression A therosclerosis and its clinical sequelae, coronary heart disease, stroke, and peripheral vascular disease, represent significant medical problems. In the United States, approximately 13 million patients have diagnosed coronary heart disease, and almost 800 000 deaths in 2007 were due to cardiovascular disease or its complications. 1 Despite recent advances in pharmacological intervention, identification and prevention of processes leading to atherosclerotic plaque rupture remain incomplete. Understanding the molecular mechanisms that drive this process is a critical step toward development of therapies to slow or reverse progression of atherosclerosis. Clinical Perspective on p 604Currently, few validated targets are available for pharmacological treatment of atherosclerosis, and a limited number of diagnostic techniques can accurately predict either plaque progression or response to treatment. Gene expression microarray technology and systems biology allow comprehensive characterization of the pathological processes associated with atherosclerosis, making possible the identification of new targets to treat this disease and new diagnostic measures of disease progression. 2 To understand the underlying disease pathophysiology and gain insights into plaque biology that could facilitate the discovery of new therapies, we have undertaken gene expression profiling of human plaque. Because of its availability and documented similarity ...

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