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Abstract: Host defense peptides (HDPs) are well‐characterized for their antimicrobial activities but also variously display potent immunomodulatory effects. Human β‐defensin 3 (HBD‐3) belongs to a well‐known HDP family known as defensins and is able to induce leukocyte chemotactic recruitment, leukocyte activation/maturation, proinflammatory cytokine release, and co‐stimulatory marker expression. HBD‐3‐stimulated cytokine induction is NF‐κB‐dependent and was initially suggested to act via G protein‐coupled C‐C chemokine receptor phospholipase C (PLC) and/or Toll‐like receptor signaling. Subsequent pharmacological inhibition, however, revealed that NF‐κB activation by HBD‐3 is receptor‐independent and instead involves the phosphoinositide 3‐kinase (PI3K)‐protein kinase B (Akt) pathway, the mechanism of which remains undetermined. Recently, we have shown that HBD‐3 can enter mammalian cells and bind to inner membrane phosphoinositide 4,5‐bisphosphate [PI(4,5)P2], an important second lipid messenger of PLC and PI3K‐Akt pathways. In this study, we report that the interaction of HBD‐3 with PI(4,5)P2 is important for PI3K‐Akt‐NF‐κΒ‐mediated induction of tumor necrosis factor and interleukin‐6. These data provide insights into the mechanism of immunomodulation by HBD‐3, and more generally, highlight the complex multifaceted signaling roles of HDPs in innate defense. Furthermore, it is suggested that the proposed mode of action may be conserved in other HDPs. [ABSTRACT FROM AUTHOR]

The MS4A (membrane-spanning 4-domain family, subfamily A) family of proteins contains some well-known members including MS4A1 (CD20), MS4A2 (FcεRIβ) and MS4A3 (HTm4). These three MS4A family members are expressed on the cell surface of specific leukocyte subsets and have been well characterized as having key roles in regulating cell activation, growth and development. However, beyond MS4A1-3 there are a large number of related molecules (18 to date in humans) where our understanding of their biological roles is at a relatively nascent stage. This review examines the larger MS4A family focusing on their structure, expression, regulation and characterized and/or emerging biological roles. Our own work on one family member MS4A8B, and its possible role in epithelial cell regulation, is also highlighted. [ABSTRACT FROM AUTHOR]

Heparanase (HPSE) is an endoglycosidase that cleaves heparan sulfate (HS) and plays an important role in tumor metastasis, angiogenesis and inflammation. The regulation of HPSE expression and function is tightly controlled and the increasing use of the mouse as an animal model to define the role of HPSE in many physiological and pathological settings, makes understanding the regulatory mechanisms of HPSE in this species of fundamental importance. However, the expression distribution of the mouse Hpse gene and the mechanisms that regulate its transcription are poorly defined. In this study, the mouse Hpse gene was determined to encode for two mRNA transcripts of 1.9 and 3.2 kb in length with identical open reading frames that showed similar tissue expression distribution to the human HPSE. The mouse Hpse promoter was cloned and a 478-bp minimal promoter was identified that contained regulatory elements responsible for both basal promoter activity in mouse tumor cells as well as inducible activity in T cells. Mutagenesis and transactivation studies identified a functional site in the minimal promoter region for the transcription factor Early growth response gene 1 (Egr1). Interestingly, Egr1 acted differentially in mouse tumor cells, functioning in an activating or repressive manner in breast carcinoma or melanoma cells, respectively. Furthermore, the proximal region of the promoter, identified as important in the regulation of Hpse transcription, was shown to become accessible in T cells upon cell activation. Significantly, the maximal accessibility of the promoter occurred at 16 h post-stimulation, which correlated with the induction kinetics of Hpse mRNA expression. In summary, this study demonstrates that mouse Hpse is expressed and regulated in a similar manner to human HPSE and also provides some novel insights into mechanisms of Hpse gene regulation that are likely to be relevant to control of the human gene.Immunology and Cell Biology (2007) 85, 205–214. doi:10.1038/sj.icb.7100022; published online 9 January 2007 [ABSTRACT FROM AUTHOR]

Summary Haematopoietic cell-specific transmembrane-4 (HTm4) is a four-transmembrane protein most closely related to CD20 and the beta subunit of the high affinity receptor for IgE (FcℇRIβ). To date, it has only been described in humans, where it is expressed in haematopoietic cells of both myeloid and lymphoid lineages. The function of HTm4 is unknown; however, as for CD20 and FcℇRI-β, it is likely to play a role in signal transduction as part of a multi-subunit cell surface receptor complex. In this study, we report the cDNA cloning and expression distribution of mouse HTm4. The deduced mouse HTm4 protein is of 213 amino acids, and contains four putative transmembrane domains. Mouse HTm4 shows 62% overall amino acid identity with human HTm4; the transmembrane regions are highly conserved between both species (75% identity), whereas the N- and C-terminal and inter-transmembrane loop regions are more divergent (52%). Interestingly, the N-terminal domain of mouse HTm4 is predicted to be 23 amino acids shorter, and the C-terminal domain 23 amino acids longer, than that of human HTm4. Northern blot and reverse transcriptase (RT)-PCR analysis suggest that mouse HTm4 mRNA is expressed at low levels only in spleen, bone marrow and peripheral blood leucocytes. This is the first report of the cloning of HTm4 from a species other than human, and provides important sequence information towards the understanding of the function of this poorly characterized four-transmembrane molecule. [ABSTRACT FROM AUTHOR]

Summary Haematopoietic cell-specific transmembrane-4 (HTm4) is a four-transmembrane protein most closely related to CD20 and the beta subunit of the high affinity receptor for IgE (FcℇRIβ). To date, it has only been described in humans, where it is expressed in haematopoietic cells of both myeloid and lymphoid lineages. The function of HTm4 is unknown; however, as for CD20 and FcℇRI-β, it is likely to play a role in signal transduction as part of a multi-subunit cell surface receptor complex. In this study, we report the cDNA cloning and expression distribution of mouse HTm4. The deduced mouse HTm4 protein is of 213 amino acids, and contains four putative transmembrane domains. Mouse HTm4 shows 62% overall amino acid identity with human HTm4; the transmembrane regions are highly conserved between both species (75% identity), whereas the N- and C-terminal and inter-transmembrane loop regions are more divergent (52%). Interestingly, the N-terminal domain of mouse HTm4 is predicted to be 23 amino acids shorter, and the C-terminal domain 23 amino acids longer, than that of human HTm4. Northern blot and reverse transcriptase (RT)-PCR analysis suggest that mouse HTm4 mRNA is expressed at low levels only in spleen, bone marrow and peripheral blood leucocytes. This is the first report of the cloning of HTm4 from a species other than human, and provides important sequence information towards the understanding of the function of this poorly characterized four-transmembrane molecule. [ABSTRACT FROM AUTHOR]