As part of a study to identify novel genes associated with macrophage activation, we have cloned a new member of the transforming growth factor ␤ (TGF-␤) superfamily designated macrophage inhibitory cytokine 1 (MIC-1). MIC-1 is synthesized as a 62-kDa intracellular protein, which, after cleavage by a furin like protease, is secreted as a 25-kDa disulfide-linked dimeric protein. Sequence analysis indicates that it does not cluster within any existing TGF-␤ families, suggesting it may be the first member of a new grouping within the TGF-␤ superfamily. Tissue Northern blots show that MIC-1 transcripts are only found abundantly in placenta, although smaller amounts are seen in a limited number of other adult and fetal tissues. MIC-1 is not expressed in resting macrophages but is induced by a number of different activation agents, including phorbol myristate acetate, interleukin 1, tumor necrosis factor ␣, and macrophage colony-stimulating factor but not by lipopolysaccharide or interferon-␥. We have hypothesized that it may be an autocrine inhibitor of macrophage activation but its major biological role is still uncertain.J. Leukoc. Biol. 65: 2-5; 1999.

Macrophage inhibitory cytokine (MIC‐1), a divergent member of the transforming growth factor‐β (TGF‐β) superfamily and activation associated cytokine, is secreted as a 28 kDa dimer. To understand its secretion, we examined its processing in MIC‐1‐transfected Chinese hamster ovary cells. Mature MIC‐1 dimer arises post‐endoplasmic reticulum (ER) by proteolytic cleavage of dimeric pro‐MIC‐1 precursor at a furin‐like site. Unlike previously characterized TGF‐β superfamily members, MIC‐1 dimers are also secreted in constructs lacking the propeptide. A clue to the function of the propeptide came from the observation that a range of proteasome inhibitors, including lactacystin and MG132, cause major increases in levels of undimerized pro‐MIC‐1 precursor. There was no effect of proteasome inhibitors on cells expressing mature MIC‐1 without the propeptide, suggesting that the propeptide can signal misfolding of MIC‐1, leading to proteasomal degradation. Deletion mutagenesis showed the N‐terminal 28 amino acids of the propeptide are necessary for proteasomal degradation. This is the first demonstration, to our knowledge, of a quality control function in a propeptide domain of a secretory protein and represents an additional mechanism to ensure correct folding of proteins leaving the ER.

Atrial fibrillation (AF), the most common cardiac arrhythmia, is a major contributor to population mortality and morbidity, particularly stroke-risk. 1 Atrialtissue fibrosis is a central pathophysiological feature and hampers AF-treatment; the underlying molecular mechanisms are poorly understood and present therapies are inadequate. 2 Here, we show that calcitonin (CT), a well-recognized hormone product of the thyroid gland involved in bone metabolism, 3 is produced in significant quantities by atrial cardiomyocytes and acts in a paracrine fashion on neighbouring collagenproducing fibroblasts to control their proliferation and secretion of extracellular matrix proteins. Global disruption of CT-receptor signalling in mice causes atrial fibrosis and increases AF susceptibility. Atrial-specific knockdown (KD) of CT in atrial-targeted liver-kinase B1 (LKB1)-KD mice promotes atrial fibrosis and prolongs/increases the number of spontaneous AF-episodes, while atrial-specific CT overexpression prevents fibrosis and AF in LKB1-KD mice. Patients with persistent AF are characterised by six-