Macrophages play a key role in both normal and pathological processes involving immune and inf lammatory responses, to a large extent through their capacity to secrete a wide range of biologically active molecules. To identify some of these as yet not characterized molecules, we have used a subtraction cloning approach designed to identify genes expressed in association with macrophage activation. One of these genes, designated macrophage inhibitory cytokine 1 (MIC-1), encodes a protein that bears the structural characteristics of a transforming growth factor  (TGF-) superfamily cytokine. Although it belongs to this superfamily, it has no strong homology to existing families, indicating that it is a divergent member that may represent the first of a new family within this grouping. Expression of MIC-1 mRNA in monocytoid cells is up-regulated by a variety of stimuli associated with activation, including interleukin 1, tumor necrosis factor ␣ (TNF-␣), interleukin 2, and macrophage colony-stimulating factor but not interferon ␥, or lipopolysaccharide (LPS). Its expression is also increased by TGF-. Expression of MIC-1 in CHO cells results in the proteolytic cleavage of the propeptide and secretion of a cysteine-rich dimeric protein of M r 25 kDa. Purified recombinant MIC-1 is able to inhibit lipopolysaccharide -induced macrophage TNF-␣ production, suggesting that MIC-1 acts in macrophages as an autocrine regulatory molecule. Its production in response to secreted proinf lammatory cytokines and TGF- may serve to limit the later phases of macrophage activation.
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.
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