Gram-negative bacteria induce proinflammatory cytokine production by monocytes in the absence of lipopolysaccharide (LPS)

Tumour necrosis factor-alpha (TNF-α), IL-1α and IL-6 production by human monocytes in response to a clinical strain of the Gram-negative encapsulated bacteria Neisseria meningitidis and an isogenic lpxA⁻ strain deficient in LPS was investigated. Wild-type N. meningitidis at concentrations between 10⁵ and 10⁸ organisms/ml and purified LPS induced proinflammatory cytokine production. High levels of these cytokines were also produced in response to the lpxA⁻ strain at 10⁷ and 10⁸ organisms/ml. The specific LPS antagonist bactericidal/permeability-increasing protein (rBPI₂₁) inhibited cytokine production induced by LPS and wild-type bacteria at 10⁵ organisms/ml but not at higher concentrations, and not by LPS-deficient bacteria at any concentration. These data show that proinflammatory cytokine production by monocytes in response to N. meningitidis does not require the presence of LPS. Therapeutic strategies designed to block LPS alone may not therefore be sufficient for interrupting the inflammatory response in severe meningococcal disease.