Can high histamine (histamine) levels cause elevated interleukin (IL) readings or vice versa?

Relationship Between Histamine and Interleukin Levels

Yes, high histamine levels can trigger elevated interleukin readings, and there is evidence of bidirectional interaction between these inflammatory mediators.

Histamine's Effects on Interleukin Production

• Histamine enhances interleukin (IL)-1-induced IL-1 gene expression and protein synthesis via H2 receptors in peripheral blood mononuclear cells 1
• This enhancement occurs at histamine concentrations of 10^-6 to 10^-4 M, with a two to threefold increase in IL-1 beta synthesis 1
• The effect is mediated specifically through H2 receptors, as demonstrated by the reversal of this effect with cimetidine (H2 antagonist) but not with diphenhydramine (H1 antagonist) 1

Mechanism of Histamine-Interleukin Interaction

• Histamine enhances and sustains IL-1 beta mRNA levels in IL-1 alpha-stimulated cells 1
• Although histamine alone does not induce IL-1 production, it amplifies the inflammatory process when combined with IL-1 2
• Histamine increases IL-1-induced IL-6 gene expression and protein synthesis, also via H2 receptors 2

Interleukin Effects on Histamine

• IL-4 (an important mediator of allergic inflammation) up-regulates histamine H1 receptor expression through increased transcription of the H1R gene via the JAK3-STAT6 pathway 3
• The effects of histamine and IL-4 are additive, creating a potential amplification loop in allergic conditions 3
• IL-16 release from human CD8+ T cells is controlled by histamine H4 and H2 receptors 4

Clinical Implications

• In inflammatory conditions, histamine and interleukins can create a self-perpetuating cycle:

  • Mast cell activation releases histamine
  • Histamine enhances IL-1 and IL-6 production
  • Increased interleukins further promote inflammation
  • Some interleukins (like IL-4) up-regulate histamine receptors

• During anaphylaxis, elevated levels of histamine, tryptase, IL-6, IL-10, and TNF-receptor 1 are associated with delayed deterioration and more severe reactions 5

• In COVID-19, SARS-CoV-2 can activate mast cells to release histamine, which increases IL-1 levels, potentially contributing to cytokine storm 2

Diagnostic Considerations

• When evaluating potential histamine-interleukin interactions:
  • Plasma histamine levels increase within 5-10 minutes of symptom onset but remain elevated only for 30-60 minutes 5
  • Urinary histamine metabolites remain increased for up to 24 hours 5
  • Serum tryptase (a marker of mast cell activation) peaks 60-90 minutes after symptom onset and persists for up to 6 hours 5
  • IL-6 levels correlate with the extent of erythema and duration of symptoms in allergic reactions 6

Therapeutic Implications

• H2 receptor antagonists (like cimetidine) may help reduce histamine-induced interleukin production 1
• Combined H1 and H2 antihistamines may be more effective than either alone in managing histamine-mediated inflammatory responses 7
• In conditions where both histamine and interleukins are elevated, targeting both pathways may be necessary for optimal control

Important Caveats

• There can be a disconnection between histamine and tryptase levels, with some patients exhibiting an increase of only one of these mediators 5
• Normal levels of tryptase or histamine do not rule out histamine-mediated inflammatory effects 7
• The relationship between histamine and interleukins is complex and context-dependent, with different patterns observed in various inflammatory conditions