C-36 peptide, a degradation product of alpha1-antitrypsin, modulates human monocyte activation through LPS signaling pathways.
alpha1-Antitrypsin (AAT), a major endogenous inhibitor of serine proteases, plays an important role in minimizing proteolytic injury to host tissue at sites of infection and inflammation. There is now increasing evidence that AAT undergoes post-translational modifications to yield by-products with novel biological activity. One such molecule, the C-terminal fragment of AAT, corresponding to residues 359-394 (C-36 peptide) has been reported to stimulate significant pro-inflammatory activity in monocytes and neutrophils in vitro. In this study we showed that C-36 peptide is present in human lung tissue and mimics the effects of lipopolysaccharide (LPS), albeit with lower magnitude, by inducing monocyte cytokine (TNFalpha, IL-1beta) and chemokine (IL-8) release in conjunction with the activation of nuclear factor-kappaB (NF-kappaB). Using receptor blocking antibodies and protein kinase inhibitors, we further demonstrated that C-36, like LPS, utilizes CD14 and Toll-like receptor 4 (TLR4) receptors and enzymes of the mitogen-activated protein kinase (MAPK) signaling pathways to stimulate monocyte TNFalpha release. The specificity of C-36 effects were demonstrated by failure of a shorter peptide (C-20) to elicit biological activity and the failure of C-36 to inhibit CD3/CD28-stimulated IL-2 receptor expression or proliferation in T-cells which lack TLR4 and CD14. We suggest that C-36 mediates its effects though the activation of LPS signaling pathways.
Subramaniyam
Devipriya
D
Department of Clinical Sciences, Wallenberg Laboratory, University Hospital Malmö, S-205 02 Malmö, Sweden.
Glader
Pernilla
P
von Wachenfeldt
Karin
K
Burneckiene
Jurate
J
Stevens
Tim
T
Janciauskiene
Sabina
S
D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D007239:Infections / Q000378:metabolism; D007249:Inflammation / Q000378:metabolism; D018950:Lipopolysaccharide Receptors / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008168:Lung / Q000166:cytology / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects* / Q000502:physiology; D008262:Macrophage Activation / Q000187:drug effects*; D009000:Monocytes / Q000166:cytology / Q000378:metabolism*; D010455:Peptides / Q000378:metabolism / Q000494:pharmacology*; D011499:Protein Processing, Post-Translational / Q000502:physiology; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D000515:alpha 1-Antitrypsin / Q000378:metabolism / Q000494:pharmacology*
D016207:Cytokines; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D010455:Peptides; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D000515:alpha 1-Antitrypsin