The property of neisserial IgA1 protease to induce proinflammatory cytokines may be highly relevant for the disease-causing properties of gonococci and meningococci. A hallmark of the pathophysiology in these diseases is the intense inflammatory response associated with the substantial release of proinflammatory cytokines. TNF-a, IL-1, IL-6, and IL-8 have been detected in local secretions and sera during mucosal infections with gram-negative species, in- cluding N. meningitidis and N. gonorrhoeae (29, 35). Increased levels of IL-8 and TNF-a in particular in plasma and in urine, and smaller amounts of IL-1b and IL-6 were found in experimental gonorrhea after intraurethral application of gonococci (32). High levels of these cytokines were also found in the CSF and in the serum during meningeal inflammation. These me- diators promote the inflammatory response with subsequent tissue damage and in some cases septic shock (28–30). The level of TNF-a in the CSF directly correlates with the se- verity of the damage to the blood–brain barrier (29). The most important bacterial component of gram-nega- tive bacteria known to stimulate the release of inflamma- tory cytokines is LPS. Indeed, meningococcal LPS was found to be a major cytokine-inducing component in bac- terial meningitis, since the cytokine profile and levels found in serum or CSF correlated with the LPS concentrations. However, Prins et al. (59) could not confirm the relation- ship between levels of cytokines and bacterial endotoxin produced by various strains of young meningitis patients, suggesting that factors other than endotoxin may be involved in cytokine induction during acute meningococcal septic shock. In vivo, LPS and IgA1 protease might be released together and act synergistically. Strikingly, though, the three major causative agents of bacterial meningitis, N. meningitidis, H. influenzae, and Streptococcus pneumoniae, all produce an IgA1 protease (11, 13, 14, 60). Therefore, IgA1 protease may constitute an underestimated virulence factor in sepsis and meningeal infection. Besides the cleavage of IgA1, several additional functions have been attributed to neisserial IgA1 protease. IgA1 pro- tease was recently shown to cleave LAMP-1, a lysosomal protein associated with the endosomal maturation (36, 61), but only one report suggested that, as a consequence, IgA1 protease facilitates the intracellular survival of pathogenic N. gonorrhoeae (61). Furthermore, other human proteins have been found to be proteolytic substrates in vitro. How- ever, the biological relevance of their cleavage remains un- clear. In a parallel study, we recently observed that IgA1 protease efficiently protects phagocytes from TNF-a–medi- ated apoptosis (our unpublished results). Considering the strong potential of IgA1 protease to induce TNF-a, this observation is intriguing since Neisseria is capable of enter- ing phagocytic cells by an active mechanism (62). Hence, the pathogens may have an interest in preventing lethal ef- fects of TNF-a on their intracellular niches. The induction of proinflammatory cytokines may con- tribute to the characteristic inflammatory reaction caused by the pathogenic Neisseriae. Understanding the mechanism of IgA1 protease in the regulation of these cytokines has potential therapeutic significance and is currently in progress. Future research should reveal strategies for blocking this cytokine-inducing pathway in response to pathogenic Neis- seriae and probably to other IgA1 protease–secreting human pathogenic bacteria. We thank Dr. Susanne Beck for providing the recombinant IgA1 protease, Dr. Robert Hurwitz for IgA1 protease purification and characterization, and Ilona Harm, Uwe Koscy, and Petra Lindenberg for technical assistance. We are also grateful to Drs. T. Aebischer, S. Gödert, and A. Walduck for helpful discussions. This work was supported by a grant from the Fonds der Chemischen Industrie to T.F. Meyer. Address correspondence to Thomas F. Meyer, Max-Planck-Institut für Infektionsbiologie, Abteilung Mole- kulare Biologie, Monbijoustr. 2, 10117 Berlin, Germany. Phone: 49-30-2846-0400; Fax: 49-30-2846- 0401; E-mail: meyer@mpiib-berlin.mpg.de Submitted: 22 April 1999 Revised: 8 July 1999 Accepted: 12 August 1999 References 1. Zenilman, J.M. 1993. Gonorrhea: clinical and public health issues. Hosp. Pract. 28:29–35. 2. Cartwright, K.A., and D.A. Ala’Aldeen. 1997. Neisseria men- ingitidis: clinical aspects. J. Infect. 34:15–19. 3. Cannon, J.G., and P.F. Sparling. 1984. 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