The Journal of Immunology, Vol 148, Issue 12 3937-3942, Copyright © 1992 by American Association of Immunologists

ARTICLES

Identification and characterization of the effector region within human C5a responsible for stimulation of IL-6 synthesis

EL Morgan, S Sanderson, W Scholz, DJ Noonan, WO Weigle and TE Hugli
Department of Immunology, Scripps Research Institute, La Jolla, CA 92037.

Human C fragment C5a is known to be a proinflammatory mediator and more recently shown to be a potent modulator of both humoral and cell- mediated immunity. We recently reported that natural and recombinant C5a induces the synthesis of IL-6-specific mRNA and secreted protein from human monocytes. Our studies using analogue peptides that are homologous to the carboxyl-terminal sequence of human C5a, indicate that the "effector" site for inducing IL-6 synthesis resides within the C-terminal region (C5a (70-74)) of the C5a molecule. C5a peptides containing the exact sequence of the natural factor were found to retain full agonist activity but exhibited low potency (0.01-0.1% of intact C5a). It was also shown that amino acid substitutions in the C5a peptides by aromatic/hydrophobic residues, outside the immediate effector site, resulted in analogue peptides with a substantial increase in potency relative to the most active natural peptide (C5a (56-74)). Moreover, these peptides approach the potency of natural C5a for induction of IL-6. Taken together, these results suggest that the inflammatory and immunoregulatory activities associated with C5a may, in part, be due to the synthesis of IL-6.

This article has been cited by other articles:

				M. S. Huber-Lang, J. V. Sarma, S. R. McGuire, K. T. Lu, V. A. Padgaonkar, E. M. Younkin, R. F. Guo, C. H. Weber, E. R. Zuiderweg, F. S. Zetoune, et al. Structure-Function Relationships of Human C5a and C5aR J. Immunol., June 15, 2003; 170(12): 6115 - 6124. [Abstract] [Full Text] [PDF]

				J. T. Ulrich, W. Cieplak, N. J. Paczkowski, S. M. Taylor, and S. D. Sanderson Induction of an Antigen-Specific CTL Response by a Conformationally Biased Agonist of Human C5a Anaphylatoxin as a Molecular Adjuvant J. Immunol., May 15, 2000; 164(10): 5492 - 5498. [Abstract] [Full Text] [PDF]

				M. Wittmann, J. Zwirner, V.-A. Larsson, K. Kirchhoff, G. Begemann, A. Kapp, O. Gotze, and T. Werfel C5a Suppresses the Production of IL-12 by IFN-{gamma}-Primed and Lipopolysaccharide-Challenged Human Monocytes J. Immunol., June 1, 1999; 162(11): 6763 - 6769. [Abstract] [Full Text] [PDF]

				W. A. Wilmer, P. T. Kaumaya, J. A. Ember, and F. G. Cosio Receptors for the Anaphylatoxin C5a (CD88) on Human Mesangial Cells J. Immunol., June 1, 1998; 160(11): 5646 - 5652. [Abstract] [Full Text] [PDF]

				Z. Chen, X. Zhang, N. C. Gonnella, T. C. Pellas, W. C. Boyar, and F. Ni Residues 21-30 within the Extracellular N-terminal Region of the C5a Receptor Represent a Binding Domain for the C5a Anaphylatoxin J. Biol. Chem., April 24, 1998; 273(17): 10411 - 10419. [Abstract] [Full Text] [PDF]

				G. L. Kukielka, C. W. Smith, A. M. Manning, K. A. Youker, L. H. Michael, and M. L. Entman Induction of Interleukin-6 Synthesis in the Myocardium : Potential Role in Postreperfusion Inflammatory Injury Circulation, October 1, 1995; 92(7): 1866 - 1875. [Abstract] [Full Text]